UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: I 0 May 2016 

SUBJECT: Fluensulfone - Aggregate Human Health Risk Assessment Addressing Label 

Amendments, Changes to the Residue Definition, and New Uses on Multiple 

Crops. 

FROM: 

PC Code: 0504 I 0 

Decision Nos.: 50 I 793, 507767, 508627, 509477 

DP Barcodes: D427486, D428909, 

D429293, D42980 I 

Registration Nos.: 66222-243, 66222-

EAE, 53883-GL T 

Petition Nos.: 5F835 I, 5E8384 Regulatory Actions: Section 3 Registration 

and Label Amendments 

Risk Assessment Type: Single Chemical Aggregate Case No.: NA 

TXR No.: NA CAS No.: 3 I 8290-98- I 

MRJD No.: See Attachment I 40 CFR: I 80.680 

Michael A. Doherty, Ph.D., Senior Chemi~t . t{]J / JJanet 

Jaime 

Cowins, 

D' Agostino, 

Ph.D., 

Ph.D., 

Chemist 

Toxicologist .._~ ~ 

• ~ 

Zaida Figueroa, DrPH .. Industrial Hygienist 

Gerad Thornton, Environmental Protection Specialist 

Risk Assessment Branch II 

Health Effects Division (7509P) 

THROUGH: Christina Swartz, Chief I} n ' /\ ,.--

Risk Assessment Branch II ~ ~ 

Health Effects Division (7509P) 

TO: Rita Kumar/Mark Suarez/Meredith Laws 

Invertebrate and Vertebrate Branch 3 

Registration Division (7505P) 

Andrew Ertman/Barbara Madden/Marion Johnson 

Risk Integration, Minor Use, and Emergency Response Branch 

Registration Division (7505P) 

Page 1 of 57 
Fluensulfone D427486 

1.0 Executive Summary ............................................................................................................. 4 

2.0 HED Recommendations ....................................................................................................... 6 

2. l Data Deficiencies ............................................................................................................. 6 

2.2 Tolerance Considerations ................................................................................................. 6 

2.2.1 Enforcement Analytical Method ............................................................................... 7 

2.2.2 Recommended Tolerances .. ...................................................................................... 7 

2.2.3 Revisions to Petitioned-For Tolerances .................................................................... 7 

2.2.4 International Harmonization ..................................................................................... 8 

2.3 Label Recommendations .................................................................................................. 9 

2.3.1 Recommendations from Residue Reviews ............................................................... 9 

2.3.2 Recommendations from Occupational Assessment.. ................................................ 9 

2.3.3 Recommendations from Residential Assessment ................................................... I 0 

3.0 Introduction ........................................................................................................................ 10 

3.1 Chemical Identity ........................................................................................................... 10 

3.2 Physical/Chemical Characteristics ................................................................................. 11 

3.3 Pesticide Use Pattern ...................................................................................................... 11 

3 .4 Anticipated Exposure Pathways .................................................................................... 14 

3.5 Consideration of Environmental Justice ........................................................................ 14 

4.0 Hazard Characterization and Dose-Response Assessment ................................................ 15 

4.1 Summary of Toxicological Effects ................................................................................ 15 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ................................... 16 

4.2. 1 Dermal Absorption ..................................................... ............................................. 16 

4.3 Toxicological Effects ..................................................................................................... 17 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) .................................. .... 19 

4.4.1 Completeness of the Toxicology Database ............................................................. 19 

4.4.2 Evidence of Neurotoxicity ...................................................................................... 20 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 20 

4.4.4 Residual Uncertainty in the Exposure Database ..................................................... 20 

4.5 Toxicity Endpoint and Point of Departure Selections ................................................... 20 

4.5. l Dose-Response Assessment .................................................................................... 20 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment.. ...... 23 

4.5.3 Cancer Classification and Risk Assessment Recommendation .............................. 24 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment ............................................................................................................................ 24 

5.0 Dietary Exposure and Risk Assessment.. ............................. .............................................. 26 

5.1 Residues of Concern Summary and Rationale ............................................................... 26 

5.2 Food Residue Profile ....................................................................... ............................... 27 

5.3 Water Residue Profile .................................................................................................... 27 

5 .4 Dietary Risk Assessment ............................................................................................... 28 

5.4.1 Description of Residue Data Used in Dietary Assessment.. ................................... 28 

5.4.2 Percent Crop Treated Used in Dietary Assessment ...... .......................................... 28 

5.4.3 Acute and Chronic Dietary Risk Assessment ...................... ................................... 28 

6.0 

6. l 

6.2 

6.3 

Residential (Non-Occupational) Exposure/Risk Characterization ..................................... 29 

Residential Handler Exposure ........... ......................... .................................................... 29 

Post-Application Exposure ............................................................................................ 29 

Residential Risk Estimates for Use in Aggregate Assessment ...................................... 30 

Page 2 of 57 
Fluensulfone D427486

Page 3 of 57

7.0 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk Estimates 31

8.0 Non-Occupational Spray Drift Exposure and Risk Estimates............................................ 31

9.0 Aggregate Exposure/Risk Characterization ....................................................................... 32

9.1 Acute Aggregate Risk .................................................................................................... 32

9.2 Short-Term Aggregate Risk........................................................................................... 32

9.3 Intermediate-Term Aggregate Risk ............................................................................... 32

9.4 Chronic Aggregate Risk................................................................................................. 32

9.5 Cancer Aggregate Risk .................................................................................................. 33

10.0 Cumulative Exposure/Risk Characterization ..................................................................... 33

11.0 Occupational Exposure/Risk Characterization................................................................... 33

11.1 Short-Term Handler Risk............................................................................................... 33

11.2 Short-Term Post-Application Risk ................................................................................ 37

11.2.1 Dermal Post-Application Risk ................................................................................ 37

11.2.2 Inhalation Post-Application Risk............................................................................ 39

12.0 References.......................................................................................................................... 39

Attachment 1. Fluensulfone bibliography to support label amendments and new uses. .............. 41

Appendix A. Toxicology Profile and Executive Summaries........................................................ 42

A.1 Toxicology Data Requirements ..................................................................................... 42

A.2 Toxicity Profiles............................................................................................................. 43

Appendix B. Physical/Chemical Properties.................................................................................. 56

Appendix C. Review of Human Research .................................................................................... 57
Fluensulfone D427486

Page 4 of 57

1.0 Executive Summary

Fluensulfone {5-Chloro-2-[(3,4,4-trifluoro-3-buten-1-yl)sulfonyl]thiazole} is a nematicide in the 

fluoroalkenyl class. Fluensulfone is currently registered for use on members of the cucurbit and 

the fruiting vegetables crop groups (Group 9 and Group 8-10, respectively), and HED recently 

evaluated a request to register fluensulfone for use on turf and sod.

The Agency has received petitions from ADAMA Agricultural Solutions, Ltd. and from IR-4 to 

register a granular (G) formulation of the nematicide fluensulfone on Crop Subgroup 1B (root 

vegetables, except sugar beet) and Crop Subgroup 1C (tuberous and corm vegetables), and the 

emulsifiable concentrate (EC) formulation on Crop Group 4 (leafy vegetables, except Brassica

leafy vegetables), Crop Group 5 (Brassica leafy vegetables), Crop Subgroup 13-07G (lowgrowing berries), Japanese white radish (daikon), turnip, and tobacco.

In separate submissions, ADAMA has requested 1) a revision to the tolerance expression in 40 

CFR 180.680; and 2) amendments to the label for Fluensulfone 480EC to increase the 

application rate on cucurbit and fruiting vegetable crops and to change the rotational crop plantback restriction intervals. For both granular and EC formulations, and for all registered and 

requested food crops, ADAMA has proposed a single application to be made pre-plant/pretransplant at a maximum rate of 3.5 lb a.i./A (EC) or 3.6 lb a.i./A (G), and the applied material is 

to be incorporated into the soil immediately after planting.

Exposure to fluensulfone in mammals results in effects on the hematopoietic system (decreased 

platelets, increased white blood cells, hematocrit, and reticulocytes), kidneys, and lungs. 

Changes in clinical chemistry as well as in body weight were also observed across multiple 

studies and species. An acute neurotoxicity screening assay showed evidence of potential 

neurotoxicity; however, neurotoxic effects were not observed in any other study, including a 

subchronic neurotoxicity study. Evidence of potential qualitative, but not quantitative, increased 

susceptibility of infants and children to the effects of fluensulfone was observed in the twogeneration reproduction study in rats, in which pup loss was observed at a dose that resulted in 

less severe (body weight) effects in the dams. No evidence of either qualitative or quantitative 

susceptibility was observed in developmental toxicity studies in rats or rabbits. Dietary and 

inhalation studies in rats showed evidence of portal-of-entry effects in the forestomach, pharynx, 

epiglottis, and nasal cavity. Overall, the most sensitive endpoints for assessing human health risk 

are the increased pup-loss effects for acute dietary exposure; body weight, hematological and 

clinical chemistry changes for chronic dietary as well as dermal exposures (short/intermediate 

term); and clotting time, decreased thymus weight, and portal-of-entry effects (histopathology of 

the epiglottis and nasal cavity) for inhalation exposures (short/intermediate term).

For assessing occupational oral and dermal exposures, the standard inter- and intra-species 

uncertainty factors of 10X are appropriate and result in a level of concern (LOC) of 100. For 

assessing occupational inhalation exposure, the use of a reference concentration for humans 

(RfC) supports reducing the interspecies factor to 3X; however, an additional 10X factor is 

required because a no-observed-adverse-affect level (NOAEL) was not found for the portal-ofentry effects, resulting in an LOC of 300. Given the different endpoints at the regulatory points 

of departure for the dermal and inhalation routes of exposure, risk estimates from these two 
Fluensulfone D427486

Page 5 of 57

routes were not combined. Based on the completeness of the toxicity data, the use of the most 

sensitive endpoints for risk assessment and the resulting low degree of concern regarding the 

observed qualitative susceptibility, and the conservatisms in the exposure assessments, HED has

reduced the required Food Quality Protection Act Safety Factor (FQPA SF) from 10X to 1X. 

The proposed new uses are supported by adequate residue data. Quantifiable residues of the BSA 

metabolite, which is the residue defined for enforcement, are expected in all food and feed 

commodities following treatment with fluensulfone. Residues of fluensulfone per se, which is 

the residue defined for assessing risk, were below the limit of quantification (LOQ; 0.01 ppm) in 

all field trial results except those from carrot, celery, head lettuce, and leaf lettuce. HED has 

evaluated dietary exposure to fluensulfone, taking into account all registered and proposed uses 

and estimated residues in drinking water from those uses (D432134, 29 March 2016, J. Cowins). 

Dietary (food and water) risk estimates for fluensulfone are not of concern for both acute and 

chronic exposure durations. 

In order to assess the requested application rates, HED evaluated the originally submitted field 

trials for cucurbit and fruiting vegetables; ADAMA’s proposed revised endpoint and dose for 

dermal risk assessment, including a revised dermal absorption factor (DAF) derived from new 

studies; and an occupational chemigation survey conducted by ADAMA to support a proposed 

revision to the assumption for the number of acres treated for occupational mixer/loaders. For the 

rotational crop plant-back restrictions, HED reviewed data from field rotational crop studies 

submitted with the request. The available data support the requested application rates for all 

crops, but do not support the requested rotational crop plant-back intervals.

The use of fluensulfone on turf may result in short-term residential exposures for persons present 

in treated areas after application (i.e., post-application). Routes of exposure are dermal for postapplication activities for adults, youth and children, and incidental oral (post-application) for 

children only. Due to changes in toxicological points of departure for the dermal route of 

exposure, HED reassessed residential exposure and risk as part of this risk assessment. 

Residential risk estimates for fluensulfone are not of concern for adults and children engaged in 

post-application activities on treated turf. Further, aggregate risk estimates from combined 

dermal and oral exposures, including food and drinking water sources, are not of concern. 

For occupational scenarios, long-term exposures (> 6 months) are not expected to occur; 

however, short-term (1-30 days) and intermediate-term (1-6 months) exposures may occur. With 

the use of the submitted chemigation survey data, there are no dermal risk estimates of concern 

for mixer/loaders for chemigation; in addition, there are no dermal risk estimates of concern for 

the proposed new uses. For both formulations, HED identified potential occupational 

mixer/loader/applicator inhalation risk estimates below the level of concern (LOC, i.e., margins 

of exposure (MOEs) < 300) for most scenarios with no respirators. There is no labelrecommended personal protective equipment (PPE) for respiratory protection. Mitigation 

through the use of respirators or engineering controls achieved MOEs of greater than or 

approximately equal to the LOC of 300. Dermal risk estimates were not of concern for all 

scenarios, including handler and post-application scenarios, at the label-recommended attire and 

PPE (i.e., long-sleeved shirts, long pants, shoes plus socks and chemical-resistant gloves).
Fluensulfone D427486

Page 6 of 57

Potential areas of environmental justice concerns were considered in this human health risk 

assessment to the extent possible. For more information, see Section 3.5.

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. Those studies are subject to ethics review, 

have received that review, and are compliant with applicable ethics requirements.

The most recent risk assessment for fluensulfone was conducted in 2016 (D424168, 6 January 

2016, M. Doherty et al.), to support a proposed use on turf.

2.0 HED Recommendations

HED has identified some occupational exposure scenarios with MOEs below the LOC. The 

MOEs can be mitigated with the addition of PPE. Provided RD ensures that appropriate PPE is 

specified on the subject labels, there are no human health risk issues that would preclude 

granting the requested label amendments, changing the established tolerance definition, or 

establishing new tolerances on the requested commodities. Specific recommendations are 

discussed in the sections below.

2.1 Data Deficiencies

None.

2.2 Tolerance Considerations

HED has reviewed the petitioned-for tolerances and changes to established tolerances, and has 

recommended appropriate tolerance levels in Table 2.2.2. 

The request to change the tolerance expression is acceptable. HED is recommending the 

tolerance expression in 40 CFR 180.680(a) be changed to remove the stipulation that compliance 

be in terms of fluensulfone; to wit:

(a) General. Tolerances are established for residues of the nematicide fluensulfone, 

including its metabolites and degradates, in or on the commodities in the table below. 

Compliance with the tolerance levels specified below is to be determined by measuring 

only 3,4,4-trifluoro-but-3-ene-1-sulfonic acid.

The change in the tolerance expression would result in a decrease in tolerance levels for the 

existing tolerance listings by a factor of 1.5. However, due to the concomitant increase in the 

application rate by a relative factor of 1.4 and the rounding within the OECD MRL calculation 

procedures, the net result is that the existing tolerance levels for residues in cucurbit vegetables 

(Crop Group 9) and fruiting vegetables (Crop Group 8-10) should not be changed despite the 

change in the tolerance expression.

Furthermore, HED notes that the time-limited tolerance associated with the Section 18 use on 

carrot (40 CFR 180.680(b)) should be removed upon establishment of a permanent tolerance for 

residues of fluensulfone in or on Crop Group 1B, which includes carrot.
Fluensulfone D427486

Page 7 of 57

2.2.1 Enforcement Analytical Method

An acceptable analytical method for enforcement was evaluated with the initial fluensulfone 

submission. That method uses acetonitrile/water (1:1, v/v) extraction and analysis by reversephase HPLC-MS/MS. For analysis of the BSA metabolite (3,4,4-trifluoro-but-3-ene-1-sulfonic 

acid), which is the sole analyte for enforcement purposes, there is no clean-up in the method 

aside from filtration. The limit of quantification (LOQ), defined as the lowest limit of method 

validation, is 0.01 ppm. That same method was used to analyze all samples related to the current 

petitions. Based on concurrent recoveries, the method is deemed adequate for tolerance 

enforcement for the new use commodities.

2.2.2 Recommended Tolerances

Table 2.2.2. Tolerance Summary for Fluensulfone.

Commodity Established/

Proposed Tolerance 

(ppm)

HEDRecommended 

Tolerance (ppm)

Comments

(correct commodity definition)

Revision due to Change in Tolerance Expression and Rate Increase

Vegetables, cucurbits, group 9 0.50 0.50 No numerical change

Vegetables, fruiting, group 8-10 0.50 0.50 No numerical change

Tomato, paste 1.0 1.0 No numerical change

New Uses (Petitions 5F8351 and 5E8384)

Root vegetables, subgroup 1B, 

except sugar beet and oriental radish

3.3 3.0 Vegetables, root, except sugar 

beet, subgroup 1B

Radish, oriental 0.50 None Oriental radish is a member of crop 

subgroup 1B.

Leaves of Root and Tuber 

Vegetables, group 2

20 30 Vegetables, leaves of root and 

tuber, group 2, except sugar beet

Vegetable, tuberous and corm 0.6 0.50 Vegetables, tuberous and corm, 

subgroup 1C

Potato granules/flakes Not proposed 0.80 Potato, granules/flakes

Potato chips Not proposed 0.60 Potato, chips

Leafy Vegetables, group 4, except 

Brassica Vegetables) 

2.6 2.0 Vegetables, leafy, except Brassica,

Group 4

Head and Stem Brassica subgroup 

5A

1.3 1.50 Brassica, head and stem, subgroup 

5A

Leafy Brassica greens subgroup 5B 13 9.0 Brassica, leafy greens, subgroup 

5B

Berry, low growing, subgroup 13-

07G

0.3 0.30 Berry, low growing subgroup 13-

07G

2.2.3 Revisions to Petitioned-For Tolerances

Most of the petitioned-for tolerance levels differ from those being established by the Agency. In 

the cases of the tolerances proposed by ADAMA, it is not clear to the Agency how the tolerance 

levels proposed in the 16 March 2016 notice of filing (Federal Register 2016-05952) were 

derived. EPA’s tolerance levels are based on residues of BSA only, without any conversion to 

fluensulfone equivalents. The Agency used the OECD MRL procedures to derive the levels 

being established in today’s action. For crop groups, and per EPA’s current policy, tolerance 
Fluensulfone D427486

Page 8 of 57

levels for each representative commodity were calculated separately, and then the maximum 

value within each crop group was selected as the tolerance level. For root vegetables except 

sugar beet (Subgroup 1B), the tolerance level is based on data from radish root (including 

Oriental radish root). Although a separate listing for Oriental radish was requested, EPA is not 

establishing a separate tolerance level since that crop is a member of crop subgroup 1B. For 

leaves of root and tuber vegetables (Crop Group 2), EPA is establishing a tolerance for residues 

in/on the leaves of root and tuber vegetable, except sugar beet because the petitioned-for uses do 

not include a use on sugar beet; the tolerance is based on data from radish tops (including 

Oriental radish tops). The tolerance for residues in/on leafy vegetables except Brassica 

vegetables (Group 4) is based on data from leaf lettuce and spinach, assessed separately. For 

head and stem Brassica (Subgroup 5A), the tolerance is based on data from cabbage. For 

Brassica leafy greens (Subgroup 5B), data from mustard greens, komatsuna (Japanese mustard 

spinach), and mizuna (Japanese mustard) were combined to derive the tolerance level. Finally, 

the EPA’s tolerance level for residues in/on low growing berries (Subgroup 13-07G) is based on 

residue data from strawberry. All of EPA’s tolerance levels are expressed to provide sufficient 

precision for enforcement purposes, and this may include the addition of trailing zeros (e.g., 0.30 

ppm rather than 0.3 ppm).

In the case of the tolerance proposed by IR-4, the petitioned-for tolerance is based on the sum of 

residues of BSA and TSA, expressed as fluensulfone, rather than on residues of BSA only, which 

is how the Agency regulates residues of fluensulfone. Basing enforcement on BSA alone 

provides a suitable marker of use, simplifies residue analysis, and avoids complications that may 

result from the potential for TSA to carry over in treated soil from one year to the next. 

Furthermore, IR-4 did not propose tolerances for residues of fluensulfone in processed potato 

commodities. The submitted potato processing study indicates that during processing, residues of 

BSA in chips and in granules/flakes are likely to concentrate to levels greater than in tubers. 

Therefore, EPA is establishing separate tolerances to cover residues in those commodities.

2.2.4 International Harmonization

The current tolerance expression for fluensulfone (40 CFR 180.680) specifies that compliance 

“...is to be determined by measuring only 3,4,4-trifluoro-but-3-ene-1-sulfonic acid, calculated as 

the stoichiometric equivalent of fluensulfone.” The registrant has petitioned the Agency to revise 

the tolerance expression to be in terms of 3,4,4-trifluoro-but-3-ene-1-sulfonic acid, the BSA 

metabolite, per se in order to harmonize with the residue definition established by Codex. In 

addition, the registrant has petitioned the Agency to increase the application rate for use on 

cucurbit and fruiting vegetables from 2.5 lb ai/A to 3.5 lb ai/A. HED has re-examined the data 

from the cucurbit and fruiting vegetable field trials, which were conducted at an application rate 

of 3.5 lb ai/A. There is no numerical change to the established tolerance levels for those groups 

due to the offsetting increase from the rate change (3.5 lb ai/A ÷ 2.5 lb ai/A = 1.4) and the 

decrease from the removal of the stoichiometric conversion (291.7 g/mol fluensulfone ÷ 190.1 

g/mol BSA = 1.5), and the rounding classes used in the OECD MRL calculation procedures.

Maximum residue levels (MRLs) have been established by Canada and Codex for residues of 

fluensulfone in cucurbit vegetables (0.6 ppm Canada; 0.3 ppm Codex), fruiting vegetables (0.5 

ppm Canada; 0.3 ppm Codex), and tomato paste (1.0 ppm Canada; 0.5 ppm Codex). There is a 
Fluensulfone D427486

Page 9 of 57

lack of harmonization with the Canadian MRLs due to differences in the residue definition and 

to the new, higher application rate, and with the Codex MRLs due to the new application rate.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

RD should ensure that the following issues with the labels are resolved (see D427502, J. Cowins, 

31 March 2016 for details):

 EC and G Labels. The registrant has requested that the rotational crop plant-back 

restrictions be amended to specify a plant-back interval (PBI) of 180 days for root and 

grain crops and 150 days for all other crops not on the label. The submitted data do not 

support that request and the plant-back restriction should remain at 365 days; moreover, 

the data indicate that a restriction specifying no rotation to cereal grains is required. Thus, 

HED is recommending that the rotational crop restrictions on both the EC and G labels 

for fluensulfone allow immediate plant-back to crops on either label (Crop 

Groups/Subgroups 1B, 1C, 4, 5, 8-10, 9, and 13-07G), a prohibition against rotating to 

cereal grains after treatment with either the EC or the G formulations, and 365-day 

restriction for all other crops.

 EC Label. Japanese mustard spinach and hot herb mustard are included in Crop Group 5 

and the use directions for those crops and that crop group are identical; therefore, the 

individual listings for Japanese mustard spinach and hot herb mustard can be removed 

from the label. Furthermore, there is no codified crop group called “Japanese Root 

Vegetables;” therefore, HED is recommending that the EC label be revised to remove 

reference to “Japanese Root Vegetables.” The individual listings for turnip and Japanese 

white radish (daikon) should remain on the label.

 EC Label. Under the headings for broadcast application and banded application, the 

proposed label specifies pre-plant and pre-seeding intervals of 7 and 14 days. Those 

directions are in conflict with those in the crop-specific use directions for Brassica (cole) 

leafy vegetables, Japanese mustard spinach, hot herb mustard spinach, Japanese white 

radish (daikon), and turnip, which specify that treatment occur a minimum of 30 days 

prior to transplanting or seeding. The language in the general use information section 

should be revised to correct the inconsistency.

 G Label. For the crop-specific use directions, the directions for potato, sweet potato, yam, 

and others give a crop group of “ROOT VEGETABLES (EXCEPT SUGAR BEET) 

SUBGROUP 1-C.” The correct name for Crop Subgroup 1C is “Tuberous and Corm 

Vegetables,” and the label should be revised accordingly.

2.3.2 Recommendations from Occupational Assessment

The proposed EC and G fluensulfone labels require handlers to wear baseline attire (i.e., longsleeved shirt, long pants, shoes plus socks) and PPE (i.e., chemical-resistant gloves). In addition, 

the G label requires a PF10 respirator for operators of tractor-drawn spreaders. For both 
Fluensulfone D427486

Page 10 of 57

formulations, inhalation MOEs are below the level of concern of 300 for many scenarios. For the 

majority of those cases, addition of a PF5 respirator results in MOEs greater than 300. For one 

scenario with the granular formulation (mixer/loader for tractor-drawn spreader for high-acreage 

crops), the addition of a PF10 respirator results in an MOE of 270; engineering controls are 

needed to obtain an MOE greater than 300 for this scenario. RD should ensure that appropriate 

personal protective equipment (PPE) is included on the labels to protect occupational handlers 

(i.e., PF5 or PF10 respirator, or engineering controls). Information to assess the dry bulk 

fertilizer use was not provided, and that use should be removed from the label. Furthermore, RD 

should ensure that the restricted-entry interval (REI) appears on the labels. The toxicology 

categories for fluensulfone indicate that a 12-hour REI is appropriate.

HED notes that closed systems are no longer required on the EC formulation label for mixing 

and loading activities for chemigation applications in order to mitigate handler exposure.

2.3.3 Recommendations from Residential Assessment

None

3.0 Introduction

Fluensulfone is a non-fumigant nematicide and the first active ingredient in the fluoroalkenyl 

class of pesticides. Fluensulfone shows activity in multiple nematicide physiological systems; its 

specific pesticidal mode of action is not known at this time.

3.1 Chemical Identity

Table 3.1. Fluensulfone Nomenclature.

Compound Chemical Structure

Common name Fluensulfone

Company experimental name MCW-2

IUPAC name 5-chloro-1,3-thiazol-2-yl 3,4,4-trifluorobut-3-en-1-yl sulfone

CAS name 5-chloro-2-[(3,4,4-trifluoro-3-buten-1-yl)sulfonyl]thiazole

CAS # 318290-98-1

End-use product/EP 66222-243 – Emulsifiable Concentrate (40% a.i.), 66222-EAE – Granular (15% 

a.i.)

Compound

BSA

Chemical Structure
Fluensulfone D427486

Page 11 of 57

IUPAC name 3,4,4-trifluorobut-3-ene-1-sulfonic acid

CAS name 3,4,4-trifluoro-but-3-ene-1-sulfonic acid

3.2 Physical/Chemical Characteristics

Technical-grade fluensulfone is solid at room temperature, however a phase change (from solid 

to liquid) may occur at elevated temperatures. The chemical is slightly volatile (vapor pressure = 

0.03 Pa at 25°C); therefore exposure to fluensulfone in its vaporous phase is likely. The 

technical-grade substance has a log KOW of 2.2 indicating a relatively lipophilic nature, but not to 

a degree that soil adsorption and bioaccumulation should be of concern.

Dietary exposure to the metabolites BSA and TSA is expected to be greater than that to the 

parent compound, fluensulfone. Physicochemical properties for BSA and TSA were not 

provided. As sulfonic acids, which are considered to be strong acids that exist as salts, these 

metabolites are expected to be more hydrophilic, more mobile in the soil profile, and lower in 

volatility, relative to the parent compound. 

3.3 Pesticide Use Pattern

Two formulations are being considered for the new uses of fluensulfone: a new granular 

formulation, containing 15% a.i., for use on root vegetables (except sugar beet; Crop Subgroup 

1B) and tuberous and corm vegetables (Crop Subgroup 1C), and a currently registered

emulsifiable concentrate, containing 40% a.i., for use on leafy vegetables (Crop Group 4), 

brassica vegetables (Crop Group 5), low-growing berries (Crop Subgroup 13-07G), Japanese 

white radish (daikon), turnip, and tobacco. For all uses, the annual maximum application rate is 

3.5 lb ai/A.

Table 3.3. Summary of Proposed Directions for Use of Fluensulfone.

Applic. 

Timing, Type, 

and Equip.

Formulation

[EPA Reg. 

No.]

Applic. 

Rate 

(lb ai/A)

Max. 

No. 

Applic. 

per 

Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

Applic.

Timing

Use Directions 

and Limitations

LABEL AMENDMENTS

Cucurbit Vegetables (Crop Group 9 includes: cucumbers, melons (cantaloupes, watermelon, honeydew), and squash.)

Fruiting Vegetables (Crop Group 8-10 includes: bell pepper, eggplant, ground cherry, hot pepper, pepino, pepper 

(except black), pimento, sweet pepper, tomatillo, and tomatoes for processing.)

Pre-Plant; 

Drip 

irrigation,

Band 

applicator,

Broadcast 

spray

Emulsifiable 

Concentrate

[66222-243]

1.75-3.50 

lb ai/A

(56-112 fl 

oz/A)

1-2

(depend

ing on 

rate)

3.5 lb ai/A

Apply at 

least 7 days 

before 

transplanting 

and at least 

14 days 

before 

seeding

For pre-seeding 

applications, 

make 2 

supplemental 

irrigations prior to

planting.

Do not rotate to 

cereal grains. For 

crops not on 

either the EC 

label or the G 

label, do not plant 
Fluensulfone D427486

Page 12 of 57

back for 180 days 

following 

application

NEW USES

Root vegetables (except sugar beet) Subgroup 1B – carrot, radish, turnip and other root vegetables including: 

Beet, garden; burdock, edible; celeriac; chervil, turnip-rooted; chicory; ginseng; horseradish; parsley, turniprooted; parsnip; radish, oriental; rutabaga; salsify; salsify, black; salsify, Spanish; skirret 

Pre-plant: 

broadcast or 

band treatment 

to soil

Granule

[66222-EAE]

1.78 – 3.6 

lb ai/A

[2.0 – 4.0 

kg ai/ha]

1 

appl./yr

3.6 lb ai/A

[4.0 kg ai/ha]

Apply at 

least 10 days 

before 

planting for 

seeded crops.

Do not allow 

livestock animals 

to forage/graze 

within 6 months.

Do not rotate to 

cereal grains. For 

crops not on 

either the EC 

label or the G 

label, do not plant 

back for 180 days 

following 

application

Tuberous and corm Subgroup 1C – potato and other root vegetables including: arracacha; arrowroot;

artichoke, Chinese; artichoke, Jerusalem; canna, edible; cassava, bitter and sweet; chayote (root); chufa; 

dasheen; ginger; leren; potato; sweet potato; tanier; turmeric; yam bean; yam, true

Pre-plant: 

incorporation, 

broadcast, or

banding to soil

Granule

[66222-EAE]

1.78 – 3.6 

lb ai/A

[2.0 – 4.0 

kg ai/ha]

1 

appl./yr

3.6 lb ai/A

[4.0 kg ai/ha]

Apply at 

planting or 

pre-planting.

Do not allow 

livestock animals 

to forage/graze 

within 6 months.

Do not rotate to 

cereal grains. For 

crops not on 

either the EC 

label or the G 

label, do not plant 

back for 180 days 

following 

application

Leafy Vegetables (Except Brassica Vegetables), Group 4 – Celery, lettuce (head and leaf), spinach and other 

leafy vegetables including: Amaranth; arugula; chervil; chrysanthemum, edible-leaved; chrysanthemum, 

garland; corn salad; cress, garden; cress, upland; dandelion; dock; endive; lettuce; orach; parsley; purslane, 

garden; purslane, winter; radicchio (red chicory); spinach; spinach, New Zealand; spinach, vine.

Pre-plant: 

broadcast 

spray, band 

application, or 

Drip irrigation

Emulsifiable 

Concentrate

[66222-243]

1.75 – 3.5 

lb ai/A

(56 – 112 

fl. oz./A)

[1.92-3.84 

kg ai/ha]

1 

appl./yr

3.5 lb ai/A

(112 oz./A)

[3.84 kg ai/ha]

Apply at 

least 7 days 

prior to 

transplanting 

and at least 

14 days prior 

to seeding.

Do not rotate to 

cereal grains. For 

crops not on 

either the EC 

label or the G 

label, do not plant 

back for 180 days 

following 

application 

Japanese white radish (daikon)

Turnip
Fluensulfone D427486

Page 13 of 57

Brassica (COLE) leafy vegetables Group 5 – Broccoli, cabbage, cauliflower and other brassicas including: 

broccoli, Chinese (gai lon); broccoli raab (rapini); Brussel sprouts; cabbage, Chinese (bok choy); cabbage 

Chinese (napa); cabbage Chinese mustard (gai choy); cavalo broccoli; collards; kale; kohlrabi; mizuna; 

mustard greens; mustard spinach; rape greens

Pre-plant: 

broadcast 

spray, band 

application, or 

Drip irrigation

Emulsifiable 

Concentrate

[66222-243]

1.75 – 3.5 

lb ai/A

(56 – 112 

fl. oz./A)

[1.92-3.84 

kg ai/ha]

1 

appl./yr

3.5 lb ai/A

(112 oz./A)

[3.84 kg ai/ha]

Apply at 

least 30 days 

prior to 

transplanting 

or seeding.

Do not rotate to 

cereal grains. For 

crops not on 

either the EC 

label or the G 

label, do not plant 

back for 180 days 

following 

application

Berry and Small Fruit, Subgroup 13-07G – Strawberry and Low growing berry including: Bearberry; bilberry; 

blueberry, lowbush; cloudberry; cranberry; lingonberry; muntries; partridgeberry; strawberry; cultivars, 

varieties, and/or hybrids of these

Pre-plant: 

broadcast 

spray, band 

application, or 

Drip irrigation

Emulsifiable 

Concentrate

[66222-243]

1.75 – 3.5 

lb ai/A

(56 -112 

fl. oz./A)

[1.92-3.84 

kg ai/ha]

2 

appl./yr

3.5 lb ai/A

(112 oz/A)

[3.84 kg ai/ha]

Apply at 

least 7 days 

before 

planting.

For all 

perennial 

crops, 

application 

may be split 

between 

spring and 

fall. The 

spring 

application 

must be 

made 30 days 

or more prior 

to bloom and 

the fall 

application 

must be 

made after 

harvest.

Do not rotate to 

cereal grains. For 

crops not on 

either the EC 

label or the G 

label, do not plant 

back for 180 days 

following 

application

Tobacco

Pre-plant: 

broadcast 

spray, band 

application, or 

Drip irrigation

Emulsifiable 

Concentrate

[66222-243]

1.75 – 3.5 

lb ai/A

(56 – 112 

fl. oz./A)

[1.92-3.84 

kg ai/ha]

1 

appl./yr

3.5 lb ai/A

(112 oz/A)

[3.84 kg ai/ha]

Apply at 

least 7 days 

before 

planting.

Do not rotate to 

cereal grains. For 

crops not on 

either the EC 

label or the G 

label, do not plant 

back for 180 days 

following 

application

Based on the review of the submitted residue data (J. Cowins, 31 March 2016. D427502), HED 

is recommending the following changes to the labels:
Fluensulfone D427486

Page 14 of 57

 Rotational crop restrictions on both the EC and G labels for fluensulfone allow 

immediate plant-back to crops on either label (Crop Groups/Subgroups 1B, 1C, 4, 5, 8-

10, 9, and 13-07G), a prohibition against rotating to cereal grains after treatment with 

either the EC or the G formulations, and 365-day restriction for all other crops. 

 Japanese mustard spinach and hot herb mustard are included in Crop Group 5 and the use 

directions for those crops and that group are identical; therefore, the individual listings 

for Japanese mustard spinach and hot herb mustard can be removed from the EC label.

 “Japanese Root Vegetables” are not a codified crop group; therefore, the EC label should 

be revised to remove reference to “Japanese Root Vegetables.” The individual listings for 

turnip and Japanese white radish (daikon) should remain on the label.

 The pre-plant intervals on the EC label in the general use directions section should be 

revised to be not in conflict with the intervals specified for Brassica (cole) leafy 

vegetables, Japanese white radish (daikon), and turnips.

 The name of Crop Subgroup 1C on the label for the granular formulation is incorrect and 

should be revised to say “Tuberous and Corm Vegetables Subgroup 1C.”

3.4 Anticipated Exposure Pathways

Use of fluensulfone on food crops may result in human exposures to residues via food and 

drinking water (as a result of transport of residues into ground and surface water drinking water 

supplies). In addition, the use of fluensulfone on turf (registration pending) may result in dermal, 

inhalation, and oral exposures in a residential setting. From an occupational perspective, workers 

may be exposed (dermal and inhalation) to fluensulfone during mixing, loading, and/or applying 

the pesticide. Post-application occupational exposures may also occur when workers re-enter 

treated fields.

This risk assessment considers all of these exposure pathways, taking in to account the registered 

and proposed uses of fluensulfone.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide 

exposures that are based on patterns of that subgroup’s food and water consumption, and 

activities in and around the home that involve pesticide use in a residential setting. Extensive 

data on food consumption patterns are compiled by the USDA under the Continuing Survey of 

Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered 

food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, 
Fluensulfone D427486

Page 15 of 57

season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess 

dietary exposure to smaller, specialized subgroups and exposure assessments are performed 

when conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based 

on home use of pesticide products and associated risks for adult applicators and for toddlers, 

youths, and adults entering or playing on treated areas post-application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Summary of Toxicological Effects

The toxicology database for fluensulfone is complete and acceptable for selecting toxicity 

endpoints and points of departure for risk assessment. The toxicology database includes a 

recently submitted in vitro comparative dermal absorption study with rat and human skin for the 

EC formulation to refine the dermal absorption value that was evaluated as part of the last risk 

assessment (D424168). In addition, a submission from the registrant to consider an alternative 

dermal POD was evaluated as part of this risk assessment (D429722) and taken into 

consideration for endpoint selection (see section 4.5.1).

The available toxicology studies include the following: 

 subchronic oral toxicity studies in rats, mice and dogs

 28-day dermal toxicity study in rats

 90-day inhalation study in rats

 developmental toxicity studies in rats and rabbits 

 2-generation reproduction study in rats 

 chronic toxicity studies in rats and dogs 

 carcinogenicity studies in mice and rats 

 battery of genotoxicity studies 

 dermal penetration study in rats and two in vitro comparative dermal absorption study 

with rat and human skin (all three testing an EC formulation of fluensulfone)

 acute and subchronic neurotoxicity studies in rats

 an immunotoxicity study in mice

 multiple ADME studies in rats

 acute oral, dermal, and inhalation toxicity studies

 primary eye and dermal irritation studies

 a dermal sensitization study

For the BSA and TSA metabolites of fluensulfone, toxicology studies include:

 acute oral studies in rats

 28-day oral studies in rats

 bacterial and mammalian cell mutagenicity studies
Fluensulfone D427486

Page 16 of 57

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

In rats, fluensulfone is rapidly absorbed following oral dosing. The time to maximum plasma 

levels (tmax) was 2-4 hours in males and females at the low dose (5 mg/kg) and 1-8 hours at the 

high dose (500 mg/kg/day). The time to maximum whole blood levels (tmax) was longer at 2-8 

hours at the low dose and 48 hours at the high dose. The difference in whole blood and plasma 

tmax is related to fluensulfone reacting with the free thiol moiety of globin in the erythrocyte. The 

majority of the dose was absorbed, as indicated by recovery of about 85% of the applied dose in 

the urine (including cage wash) at both doses tested (5 and 500 mg/kg), suggesting that there was 

no saturation of absorption. Urine was the major route of excretion accounting for 75-88% of the 

administered dose (AD) with feces accounting for 5-13% AD. Most of the AD (~80%) was 

excreted during the first 24 hours at the 5 mg/kg dose level. Fluensulfone-related compounds did 

not accumulate in tissues; the total residual radioactivity in tissues/organs was ~3.1% AD at 51 

hours post-dosing. The highest tissue levels were observed in the liver, kidney, and 

gastrointestinal tract. Identification of compounds in the urine (Table 4.2) showed no parent 

fluensulfone and indicates that fluensulfone cleaves at the sulfonyl bridge. The metabolic 

pathway begins with fluensulfone reacting with glutathione to displace butene sulfinic acid 

which is then oxidized to BSA. The glutathione adduct of the thiazole ring can then be cleaved to 

the cysteine conjugate, which is acetylated to the mercapturate. The glutathione ring is also 

cleaved to thiazole thiol (not detected in metabolism studies), which can either be oxidized to 

TSA or conjugated with glucuronic acid to give the two glucuronides. No major sex-related 

differences were observed in absorption, distribution, metabolism, or excretion.

Table 4.2. Summary of Compounds in Rat Urine Following Dosing with 14C-Fluensulfone.

Chemical Identity % of Applied Dose

Butene-Radiolabel Thiazole-Radiolabel

5 mg/kg 500 mg/kg 5 mg/kg 500 mg/kg

Fluensulfone ≤ 0.1 ≤ 0.1 ≤ 0.1 ≤ 0.1

Butene sulfinic acid 32-35 53-57 -- --

Butene sulfonic acid (BSA) 4-5 4 -- --

Thiazole mercapturate -- -- 38-40 49-54

Thiazole glucuronide I and II -- -- 24-27 20-22

Thiazole sulfonic acid (TSA) -- -- 3-5 1-3

-- = this metabolite was not detectable because it did not contain the radiolabel.

4.2.1 Dermal Absorption

Previously, a dermal absorption value was calculated using the results from an in vivo dermal 

absorption study (MRID 48574949) with the EC formulation refined by the results from an in 

vitro dermal absorption study with the EC formulation using rat and human skin (MRID 

48574950). The registrant submitted a second in vitro dermal absorption study with the EC 

formulation using rat and human skin (MRID 49700504) because they felt that a number of the 

conditions in the original study led to an overestimation of dermal absorption including: the 

occlusive nature of the application, the use of a 24-hour exposure period, and the use of an 

organic-solvent-based receptor fluid. In contrast, the newly submitted in vitro study was not 

occlusive, exposed the skin for only 8 hours, and used physiological saline as a receptor fluid. 

These parameters are in line with the OECD test guideline 428 for in vitro dermal absorption 
Fluensulfone D427486

Page 17 of 57

studies and more closely represent worker exposure conditions. Therefore, the newly submitted 

dermal absorption study is considered more relevant for risk assessment and was used to refine 

the in vivo dermal absorption value. The dermal absorption value determined with rat skin in the 

newly submitted study was considerably lower (43.6%) than that determined in the previous

study (93.5%).

The data demonstrated an inverse relationship between dosing concentration and percent 

absorption. Based on in vivo dermal absorption observed in the rat and in vitro comparative 

rat:human absorption data from the newly submitted study, an estimated human dermal 

absorption factor (DAF) of 9.5% was obtained as follows (all absorption values adjusted for 

recovery): 

(1) In the rat in vivo dermal absorption study, a dermal absorption of 58.0% (directly 

absorbed plus absorbable) was found at 24 hrs post-exposure using an application of 

0.0953 mg/cm2; 

(2) In vitro exposure of split-thickness rat skin under the same exposure and assessment 

conditions gave a dermal absorption of 43.6% (directly absorbed plus absorbable); 

(3) The ratio of the rat in vitro to the rat in vivo absorption is 0.75 (43.6/58.0) which is 

close to 1, indicating that the in vitro data is predictive of in vivo absorption; 

(4) Based on this ratio, a DAF for humans may be calculated using in vitro human dermal 

absorption (7.1%, directly absorbed plus absorbable) observed in vitro under the same 

exposure conditions. The DAF for humans is therefore 7.1%/0.75= 9.5%.

4.3 Toxicological Effects

The hematopoietic system was the major target of fluensulfone across multiple species with 

effects seen in rats, dogs, and mice. Effects on the hematopoietic system included decreased 

mean corpuscular hemoglobin, decreased mean corpuscular hemoglobin concentration, 

decreased hemoglobin, increased reticulocytes, and increased hemoglobin distribution width 

suggestive of hemolytic anemia. The hematological changes observed in the rat and dogs were 

consistent with a modest hemolytic effect of the chemical and considered minimally adverse. 

The effects appeared to be well-compensated and likely to not have a measureable effect on 

oxygen-carrying capacity under normal conditions. However, since it appeared the functional 

RBC capacity was reduced and therefore, it is plausible that there would be an effect on RBC 

function under lower-oxygen conditions or the ability of bone marrow to respond to future 

regenerative demand. While dogs appeared to be the most sensitive species in terms of effects on 

the hematopoietic system when directly comparing the NOAELs and LOAELs, effects in rat and 

dogs occurred at similar human equivalent doses following 3⁄4 body weight scaling (see section 

4.5.1 for more detail). The effects on the hematopoietic system are consistent with results from 

rat metabolism studies which demonstrate that fluensulfone can react with the free thiol moiety 

of globin, forming a covalent linkage to the thiazole group displacing butene sulfinic acid. This 

led to slower elimination of the thiazole portion of fluensulfone from whole blood (time from 

dose to 50% of peak concentration, DT50 = 6-9 days) compared to plasma (DT50 = 16-17 hours).

Other effects commonly observed in mice, rats, and dogs included changes in clinical chemistry 

parameters and decreased body weights, both of which were often seen at the LOAELs in 
Fluensulfone D427486

Page 18 of 57

subchronic and chronic studies. Altered clinical chemistry parameters included decreased plasma 

alanine amino transferase (ALAT, rats and dogs), increased cholesterol (rats), increased 

triglycerides (rats), increased phospholipids (rats), increased (mice) or decreased (dogs) 

bilirubin, decreased protein (dogs), decreased albumin and albumin/globulin ratio (dogs), 

decreased glucose (dogs), and increased TSH (dogs) in subchronic studies. 

Fluensulfone also caused effects on the kidney in male rats; however, the effects are consistent 

with accumulation of α-2-microglobulin in the kidneys which is a male rat specific process that 

is not relevant for human health risk assessment (USEPA 1991).

Effects on the lung were observed following chronic dietary exposure in mice and rats. These 

effects consisted of an increased incidence and severity of lung interstitial inflammation in the 2-

year rat study and an increased incidence of bronchiolization (change from flattened epithelium 

to cubodial epithelium) in the 18-month mouse study. Furthermore, an increased incidence of 

lung adenomas and carcinomas were observed following chronic dietary exposure to 

fluensulfone in female mice.

Fluensulfone also appeared to cause portal-of-entry effects in rats. This included the forestomach 

(diffuse basal cell hyperplasia) and pharynx (mononuclear infiltrates) in dietary subchronic 

studies; the epiglottis (squamous metaplasia, epithelial hyperplasia, and focal mononuclear cell

infiltrates) and nasal cavity (squamous epithelial hyperplasia) in the 90-day inhalation study; and 

an increased incidence/severity of acanthosis/hyperkeratosis in the 28-day dermal study. The 

dermal effects were considered adaptive due to the moderate degree of acanthosis/hyperkeratosis 

observed.

Following a single oral administration, rats exhibited decreased locomotor activity, decreased 

spontaneous activity, decreased rearing, and impaired righting response only on Day 1 in the 

acute neurotoxicity study. No evidence of neurotoxicity was observed in any other study, 

including a subchronic neurotoxicity study. Following dermal exposure for 28-days, systemic 

effects including increased reticulocytes, and increased cholesterol were observed, but only at a 

very high dose (2000 mg/kg/day, which is twice the highest dose required by the guidelines for a 

dermal study). There was no evidence of immunotoxicity in the mouse. 

No evidence of increased quantitative or qualitative susceptibility was seen in developmental 

toxicity studies in rats and rabbits. In the rat developmental toxicity study, decreased fetal weight 

was observed in the presence of decreased body weight in maternal animals. In the rabbit 

developmental toxicity study, decreased fetal weight and incomplete ossification of digit 5 of the 

medial phalanx in both forelimbs were observed in the presence of decreased body weight in 

maternal animals. In the two generation reproduction study, there was no evidence of 

quantitative susceptibility; evidence for qualitative susceptibility was manifested as decreased 

pup weight, decreased spleen weight, and an increase in post-natal pup loss [post-natal days 

(PND) 1-4] which were seen at the same dose that caused decreases in body weight in the 

parental animals.

All genotoxicity studies that were conducted on fluensulfone and three of its metabolites 

(thiazole sulfonic acid; TSA, butene sulfonic acid; BSA, and methyl sulfone; MeS) were 
Fluensulfone D427486

Page 19 of 57

negative, except for MeS with Salmonella typhimurium strain TA 100 in the absence of 

metabolic activation during a bacterial reverse mutation assay. There is little concern for the 

positive results as it was abolished by the presence of S9 and was not observed in the other tester 

strains specific for base-pair changes. Based on the results of the genetic toxicology studies, it 

was concluded that there is no mutagenic concern for fluensulfone or the fluensulfone 

metabolites tested.

Testing in acute lethality studies with fluensulfone technical-grade material resulted in low 

toxicity classifications via the oral (Toxicity Category III), dermal (Toxicity Category III), and 

inhalation (Toxicity Category IV) routes of exposure. Fluensulfone technical-grade material was 

not an irritant to eyes (Toxicity Category IV) or skin (Toxicity Category IV) but was a skin 

sensitizer. Similar results were obtained in acute lethality studies with a granular formulation 

(Appendix A.2); however, the granular formulation was determined not to be a skin sensitizer.

Oral acute lethality studies were also conducted with the metabolites MeS, BSA, or TSA, each at 

2000 mg/kg bw. By the oral route of exposure, MeS was of moderate toxicity (Toxicity Category 

II) and both BSA and TSA were of low toxicity (Toxicity Category III). HED notes that all 

animals treated with BSA or TSA survived the entire study period and that the toxicity category 

for those metabolites is based on the dosing level rather than on actual LD50 estimates. In 28-day 

rat oral toxicity studies with BSA and TSA, no treatment-related effects were observed at any 

dose (limit-dose = 1000 mg/kg/day). Based on the available data addressing toxicity of the BSA 

and TSA metabolites, the Agency has determined that they are not of toxicological concern.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The toxicology and the exposure databases for fluensulfone support a reduction of the required 

10X FQPA safety factor to 1X based on the following considerations: the completeness of the 

toxicity database including adequate studies to assess potential susceptibility in the young; there 

is no indication of quantitative susceptibility in the developmental and reproductive toxicity 

studies, and there are no residual uncertainties concerning pre- or post-natal toxicity; the 

endpoints and doses chosen for risk assessment are protective of the qualitative susceptibility 

observed in the 2-generation reproduction study; acute and subchronic neurotoxicity studies 

(ACN and SCN) are available. In addition, all endpoints used in the risk assessment are 

protective of the potential neurotoxicity observed in the ACN, and a developmental neurotoxicity 

study is not required. The dietary assessment is based on reliable data based on field trial (high 

end) residues and modeled drinking water residues, and will not underestimate exposure.

4.4.1 Completeness of the Toxicology Database

The toxicology database is considered complete and is adequate for the purpose of assessing preand postnatal susceptibility. Acceptable/guideline developmental toxicity studies in rats and 

rabbits and a reproduction study in rats, as well as acute and subchronic neurotoxicity studies in 

rats are available for FQPA assessment. A developmental neurotoxicity study is not required. 
Fluensulfone D427486

Page 20 of 57

4.4.2 Evidence of Neurotoxicity

Decreased locomotor activity in females, and decreased spontaneous activity, decreased rearing, 

and impaired righting response in both sexes were observed in the acute neurotoxicity study at 

the lowest dose tested. However, no other evidence for neurotoxicity was observed in the other 

studies in the toxicity database, including a subchronic neurotoxicity study. The doses and 

endpoints chosen for risk assessment are all protective of the effects seen in the acute 

neurotoxicity study. For example, the NOAEL for acute dietary exposure (16 mg/kg/day) from 

the 2-generation reproduction study is 6-times lower than the dose at which effects were 

observed in the acute neurotoxicity study (LOAEL = 100 mg/kg). A developmental neurotoxicity 

study is not required.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

No evidence of quantitative or qualitative susceptibility was seen in developmental toxicity 

studies in rats and rabbits. Fetal effects in those studies occurred in the presence of maternal 

toxicity and were not considered more severe than the maternal effects. However, there was 

evidence of increased qualitative, but not quantitative, susceptibility of pups in the 2-generation 

reproduction study in rats. Maternal effects observed in that study were decreased body weight 

and body weight gain; at the same dose, effects in offspring were decreased pup weights, 

decreased spleen weight, and increased pup loss (PND 1-4).

Although there is evidence of increased qualitative susceptibility in the 2-generation 

reproduction study in rats, there are no residual uncertainties with regard to pre- and/or post-natal 

toxicity following in utero exposure to rats or rabbits and pre- and/or post-natal exposures to rats. 

Considering the overall toxicity profile, the clear NOAEL for the pup effects observed in the 2-

generation reproduction study, and that the doses selected for risk assessment are protective of 

all effects in the toxicity database including the offspring effects, the degree of concern for the 

susceptibility is low. 

4.4.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database. The current dietary assessment is 

based on high-end assumptions such as tolerance-equivalent residue levels of the parent 

compound in foods, 100% crop treated, and modeled estimates of residues in drinking water. All 

of the exposure estimates are based on conservative assumptions and are not likely to 

underestimate risk.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

The toxicity endpoints and points of departure are presented in Table 4.5.4.1 and Table 4.5.4.2, 

and the details for selecting toxicity endpoints and points of departure for various exposure 

scenarios are presented in Appendix A.
Fluensulfone D427486

Page 21 of 57

For fluensulfone, HED has selected endpoints from the available data to establish points of 

departure (PODs) for the risk assessment that are protective of the observed adverse effects 

across the entire database. 

For acute dietary exposure, two studies with effects after one or two doses are available at 

similar LOAELs: pup mortality in the 2-generation reproduction toxicity study in rats (122 

mg/kg/day) and decreased motor activity in the ACN in rats (100 mg/kg/day). The POD for acute 

dietary exposure was chosen from the 2-generation reproductive toxicity study in rats. In this 

study, an increase in pup loss between PND 1 and 4 in the F1 and F2 offspring was observed at 

122.0/169.1 mg/kg/day (M/F) with a NOAEL of 16.2/23.0 mg/kg/day (M/F). The majority of the 

pup deaths occurred on post-natal day 2, although there were also a number that occurred on 

post-natal day 1. Therefore, the deaths may be attributable to a single dose. Effects observed in 

the ACN in rats also support the POD for acute dietary risk assessment. In this study, decreased 

motor activity in females and decreased spontaneous activity, decreased rearing, and impaired 

righting response in both sexes were observed at the lowest dose tested (100 mg/kg) on the day 

of dosing only. The POD was chosen from the 2-generation reproduction study over the ACN 

study with no NOAEL for the following reasons: 1) The 2-generation study had a clear NOAEL 

(16.2 mg/kg/day) for the effects observed, 2) The minimal nature of the findings at 100 

mg/kg/day is supported by the two acute LD50 studies which also reported clinical signs of slight 

severity at doses of 300 mg/kg/day, 3) The shape of the dose-response curve for the decrease in 

motor activity (a decrease of 26% at 100 mg/kg/day, 42% at 400 mg/kg/day, and 58% at 1200 

mg/kg/day) supports that an effect is not expected at a dose an order of magnitude lower (i.e., ~ 

10 mg/kg/day), and 4) Evidence of neurotoxicity was not seen in any other studies, including 

short-term gavage studies such as the developmental rat or rabbit studies. Taken together, effects 

from a single dose would not be expected to occur at a dose of 16.2 mg/kg/day and the NOAEL 

from the 2-generation reproduction study is considered protective of the effects observed in the 

ACN.

The chronic rat study was chosen for the chronic dietary endpoint over the chronic dietary 

studies from others species because the primary effects of the chemical were observed in this 

study (hematological effects, decreased body weight, and lung effects following chronic 

exposure) and the NOAEL from this study was protective of the effects observed in the other 

chronic studies. While the LOAEL of the 90-day and chronic dog studies were less than 2-fold 

higher than the chronic rat NOAEL, this is to some extent a product of dose spacing. For 

example, when the NOAELs and LOAELs are adjusted based on 3⁄4 body weight scaling, they 

are quite similar (Table 4.5.1.1). Furthermore, the effects observed in the dog studies were 

considered minimally adverse; the decreases in body weight were barely 10% in most studies 

and did not get worse over the course of the study and the effects on hematological parameters 

indicated a mild hemolytic anemia that was well-compensated for and not likely to alter the 

function of an individual under normal conditions. Taken together, HED is confident that using 

the chronic rat study is not under protective. The POD for chronic dietary exposure was based on 

a NOAEL of 9.6 mg/kg/day with decreased body weight in males, hematology and clinical 

chemistry changes, histopathological effects in the lung and esophagus at the LOAEL of 57.7

mg/kg/day. 
Fluensulfone D427486

Page 22 of 57

Table 4.5.1.1. Human Equivalent Doses (HED) based on 3⁄4 body weight scaling.

Study

Dose (mg/kg/day)

Test Species Human Equivalent (1

NOAEL LOAEL NOAEL LOAEL

Chronic rat

MRID 48574765

9.6 57.7 2.1 17.2

90-day dog

MRID 48574755 1.6 17.1 0.9 10.0

Chronic dog

MRID 48574756 3.1 16.0 1.8 10.0

1 3⁄4 body weight scaling was used to calculate a human equivalent dose (HED) using the following equation: 

[(animal body weight/human body weight)^0.25]*animal NOAEL or LOAEL. For humans, a default body 

weight of 70 kg was assumed. For rats and dogs, the average combined sex body weight at the beginning of the 

study was used.

For incidental oral exposure to children, HED also chose the chronic rat study. Although this is a 

long-term study, it is appropriate for short- and intermediate-term durations since the database 

indicates that the effects observed occurred following shorter term durations and there appeared 

to be no progression of toxicity with time based on the dog studies. While there did appear to be 

some progression in the hematological effects in the rat, the shorter term rat studies were not 

chosen because the chronic rat study included the signature effects of the chemical as part of the 

LOAEL and was consistent with the choice of the chronic study for the short- and intermediateterm dermal exposure endpoint, where the effects seen in the 28-day and 90-day study would not 

be appropriate for that endpoint (see below). Other potential studies considered for short-term 

exposure scenarios included the 28/90-day dog and 28/90-day rat studies. In the case of the dog 

studies, there appeared to be no progression of toxicity between the 90-day and 1-year study in 

which both had very similar NOAELs and LOAELs based on similar effects (decreased body 

weight and hematological changes both appearing around week 6). The 28-day dog study was 

not considered relevant for endpoint selection because of the low number of dogs used in the 

study (2 per sex) which reduced the confidence in the findings. The 90-day or 1-year dog studies 

were not chosen for a short-term endpoint because, as discussed for the chronic dietary endpoint, 

3⁄4 body weight scaling indicated that the NOAEL and LOAEL of the chronic rat study was very 

similar to the dog studies and protective of the effects while providing a slightly higher NOAEL. 

Furthermore, the effects observed in the dog in both the 90-day and 1-year study were considered 

minimally severe. Taken together, the chronic rat study is protective of the effects in the dog. 

For short- and/or intermediate-term residential/occupational exposure scenarios involving dermal 

exposure, HED did not choose the 28-day dermal toxicity study in rats conducted with the 

technical material. Although that study is of the appropriate route and duration, the results using 

the technical material do not appear to reflect the high dermal absorption of the emulsifiable 

concentrate (480 EC) observed in the in vivo and in vitro dermal penetrations studies. The dermal 

toxicity study shows minimal toxicity following exposure of 2000 mg/kg/day to technical-grade 

fluensulfone, and has a NOAEL of 400 mg/kg/day. At that NOAEL, the oral-equivalent dose 

assuming 60% absorption (approximate rat in vivo value at 10 hours) is 240 mg/kg/day, which is 

approximately 6-fold higher than the LOAELs from oral subchronic toxicity studies with rats. 

Given the lack of toxic response in the dermal toxicity study, HED has concluded that it is not 

representative of potential systemic exposure to fluensulfone from the 480 EC formulation, to 

which exposure would actually occur. Therefore, HED chose the chronic rat study discussed 
Fluensulfone D427486

Page 23 of 57

above, with a 9.5% dermal absorption factor (see Section 4.2.1), to derive the point-of-departure. 

The chronic rat study was considered appropriate for short- and intermediate-term exposure as 

described above for incidental oral exposure. In addition to the rationale provided above, the 28-

day rat and 90-day rat studies were not considered appropriate for a dermal endpoint because the 

primary effects observed at the LOAEL in each study were either α-2-microglobulin induced 

kidney effects that are not relevant for human risk assessment (28- and 90-day rat) or portal-ofentry effects that would not be expected following dermal exposure (90-day rat).

For short- and/or intermediate-term residential/occupational exposure scenarios involving 

inhalation exposure, the POD was chosen from the 90-day inhalation toxicity study in rats. In 

this study, decreased body weight, decreased thymus weight, and histopathological changes in 

the nasal cavity of males; prolonged prothrombin time in females; and histopathological changes 

in the epiglottis in both sexes were observed at the lowest dose tested (0.04 mg/L). Since a 

NOAEL could not be identified in this study, an additional 10X uncertainty factor for the use of 

a LOAEL to extrapolate to a NOAEL was applied to short- and intermediate-term inhalation 

residential/occupational exposure scenarios. 

The methods and dosimetry equations described in EPA’s reference concentration (RfC) 

guidance and OPP’s guidance on the application of the RfC methodology are suited for 

calculating human-equivalent concentrations (HECs) based on the inhalation toxicity NOAEL 

for use in margin of exposure (MOE) calculations. The regional-deposited-dose ratio (RDDR), 

which accounts for the particulate diameter (mass median aerodynamic diameter [MMAD] and 

geometric standard deviation [g] of aerosols), can be used to estimate the different dose 

fractions deposited along the respiratory tract. The RDDR is also based on interspecies 

differences in ventilation and respiratory-tract surface areas. Thus, the RDDR can be used to 

adjust an observed inhalation particulate exposure of an animal to the predicted inhalation 

exposure for a human. For the 90-day inhalation study with fluensulfone, an RDDR for the 

extrathoracic region (based on effects observed in the nasal cavity) was estimated at 0.143 based 

on the reported MMAD of 1.02 μm, standard deviation (g) of 1.59, and the respiratory-tract 

surface area of the rat relative to the human. The extrathoracic region was chosen for the RDDR 

calculation as it provides an HED which is protective of both the portal-of-entry and systemic 

effects. See section A.3.6 in Appendix 3 for the calculation of the HECs. The level of concern 

(LOC) for all exposure scenarios was 300, which includes interspecies (3X), intraspecies (10X), 

and LOAEL-to-NOAEL (10X) extrapolations. The interspecies factor was reduced from 10X to 

3X due to the HEC calculation accounting for pharmacokinetic (not pharmacodynamic) 

interspecies differences.

Long-term dermal and inhalation exposures are not expected; therefore, endpoints and doses 

were not selected. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk 

assessment must address exposures from three major sources (oral, dermal, and inhalation) and 

determine whether the individual exposures from these routes can be combined based on the 

same toxicological effects. For fluensulfone, incidental oral and dermal exposures can be 
Fluensulfone D427486

Page 24 of 57

combined since the risk assessments are based on studies with the same toxicological effects. 

While a similar systemic effect was observed in the studies used for incidental oral, dermal, and 

inhalation scenarios (decreased body weight), the derivation of the HECs used for inhalation risk 

assessment (Appendix A.3.6) show that assessing inhalation exposure based on the portal-ofentry effects is protective of the systemic endpoints since the portal-of-entry HEC is 18x lower 

than the systemic HEC. As a result, inhalation exposure should not be combined with either the 

dermal or the oral routes of exposure.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Report of the Cancer Assessment Review Committee, TXR No. 0056419, J. Rowland; K. Middleton, 7 May 2014

The Cancer Assessment Review Committee (CARC) classified fluensulfone as “Suggestive 

Evidence of Carcinogenicity” based on an increased incidence of alveolar/bronchiolar adenomas 

and carcinomas in the lung of mid- and high-dose female mice in the oncogenicity study. Tumors 

were not observed in the rat chronic toxicity/carcinogenicity study in either sex or in male mice. 

There was no evidence of genotoxicity. Although the mouse study showed that fluensulfone was 

associated with alveolar/bronchiolar adenomas and carcinomas in the female, the EPA has 

determined that quantification of cancer risk using a non-linear approach (i.e., RfD) for 

fluensulfone will adequately account for all chronic toxicity, including carcinogenicity, that 

could result from exposure to fluensulfone. That conclusion is based on the following 

considerations: (1) the tumors occurred in only one sex in one species; (2) fluensulfone and its 

metabolites are not mutagenic; and (3) no carcinogenic response was seen in either sex in the rat.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for use in Fluensulfone Dietary and NonOccupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/ 

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(All 

Populations, 

including 

Infants and 

Children and 

Females 13-49 

years of age)

Offspring 

NOAEL= 16.2 

mg/kg/day 

UFA= 10x

UFH=10x

FQPA SF= 1x

Acute RfD = 

0.16 mg/kg/day

aPAD = 0.16 

mg/kg/day

2-generation reproduction – rat

Offspring LOAEL = 122.0 mg/kg/day 

based on an increase in pup loss between 

PND 1 and 4 in the F1 and F2 offspring 

with the majority of deaths occurring on 

day 2.

Chronic 

Dietary (All 

Populations)

NOAEL = 9.6

mg/kg/day 

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD = 

0.10

mg/kg/day

cPAD = 0.10

mg/kg/day

2-year toxicity/carcinogenicity-rat

LOAEL = 57.7 mg/kg/day based on 

decreased body weight in males, and 

hematology changes, clinical chemistry 

changes and histopathological effects in 

the lung and esophagus of both sexes.
Fluensulfone D427486

Page 25 of 57

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for use in Fluensulfone Dietary and NonOccupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/ 

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Incidental Oral 

(Short-term)

NOAEL = 9.6

mg/kg/day 

(chronic dog)

UFA= 10x

UFH=10x

FQPA SF= 1x

Residential 

LOC for MOE = 

100

2-year toxicity/carcinogenicity-rat

LOAEL = 57.7 mg/kg/day based on 

decreased body weight in males, and 

hematology changes, clinical chemistry 

changes and histopathological effects in 

the lung and esophagus of both sexes.

Dermal Shortand/or

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL= 9.6

mg/kg/day 

DAF = 9.5%

UFA=10x

UFH=10x

FQPA SF= 1x

Residential 

LOC for MOE = 

100

2-year toxicity/carcinogenicity-rat

LOAEL = 57.7 mg/kg/day based on 

decreased body weight in males, and 

hematology changes, clinical chemistry 

changes and histopathological effects in 

the lung and esophagus of both sexes.

Inhalation 

Short- and/or

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL= not 

established 

(<0.04 mg/L)

HED = 0.135 

mg/kg/day

See section 

A.3.6 in 

Appendix A

for HEC and 

HED 

calculations

UFA=3x

UFH=10x

UFL=10x

FQPA SF= 1x

Residential 

LOC for MOE = 

300

90-day inhalation toxicity – rat

LOAEL = 0.04 mg/L (lowest dose tested) 

based on weight loss in males, prolonged 

prothrombin time in females, decreased 

thymus weight in males, histopathological 

changes in the epiglottis in both sexes, and 

histopathological changes in the nasal 

cavity of males. 

Cancer Classification: Suggestive evidence of carcinogenicity in humans based on lung tumors in 

female rats. The RfD is protective of potential cancer effects. 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity 

among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. FQPA SF 

= FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = 

margin of exposure. LOC = level of concern. HEC = human-equivalent concentration. HED = human-equivalent 

dose.
Fluensulfone D427486

Page 26 of 57

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for use in Fluensulfone Occupational Human 

Health Risk Assessments.

Exposure/ 

Scenario

Point of Departure Uncertainty 

Factors

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Dermal Shortand 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL= 9.6 mg/kg/day 

DAF = 9.5%

UFA=10x

UFH=10x

Occupational 

LOC for MOE 

= 100

2-year toxicity/carcinogenicity-rat

LOAEL = 57.7 mg/kg/day based on 

decreased body weight in males, 

and hematology changes, clinical 

chemistry changes and

histopathological effects in the lung 

and esophagus of both sexes.

Inhalation 

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL= not established 

(<0.04 mg/L)

HED = 0.405 mg/kg/day

See section A.3.6 in 

Appendix 3 for HEC and 

HED calculations

UFA=3x

UFH=10x

UFL=10x

Occupational 

LOC for MOE 

= 300

90-day inhalation toxicity – rat

LOAEL = 0.04 mg/L (lowest dose 

tested) based on weight loss in 

males, prolonged prothrombin time 

in females, decreased thymus 

weight in males, histopathological 

changes in the epiglottis in both 

sexes, and histopathological 

changes in the nasal cavity of 

males. 

Cancer Classification: Suggestive evidence of carcinogenicity in humans based on lung tumors in 

female mice. The RfD is protective of potential cancer effects.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to 

mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL 

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation 

from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population 

(intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. MOE = margin of exposure. LOC = level of concern. DAF = 

dermal absorption factor. HEC = human-equivalent concentration. HED = human-equivalent dose.

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale

The residue of concern for dietary assessment is the parent compound, fluensulfone. Residues of 

the metabolites BSA and TSA occur at levels significantly greater than fluensulfone; however, 

these metabolites are considered non-toxic at levels that may occur from the use of fluensulfone.

Table 5.1. Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.

Matrix Risk Assessment Tolerance Expression

Plants Primary Crop Fluensulfone BSA*

Rotational Crop Fluensulfone BSA*

Livestock Ruminant Not defined Not defined

Poultry Not defined Not defined

Drinking Water Fluensulfone + deschloro- fluensulfone + MeS* Not Applicable

* BSA refers to the butene sulfonic acid metabolite (3,4,4-trifluoro-but-3-ene-1-sulfonic acid; Company Code M3627); MeS refers to the methyl sulfone metabolite (5-chloro-2-methyl sulfonyl thiazole; Company Code M-3626).
Fluensulfone D427486

Page 27 of 57

5.2 Food Residue Profile

Residues in foods following treatment with fluensulfone typically include the metabolites BSA 

and TSA at quantifiable levels. In most field trial results, residues of fluensulfone, per se, are 

below the limit of quantification (LOQ; 0.01 ppm). Exceptions to this are trials conducted with 

carrot, celery, head lettuce, and leaf lettuce. Due to the frequency of occurrence of residues, BSA 

and TSA are better markers for enforcement than the parent compound, and due to the high 

potential for year-to-year carryover of TSA, BSA was determined to be the most appropriate 

residue for the enforcement residue definition. Both BSA and TSA have very low mammalian 

toxicity and, therefore, have been excluded from quantitative consideration in the dietary 

assessment for fluensulfone. 

Label Amendments

The petitioner requested a reduction to 150 days in the rotational crop plant-back restriction for

crops not listed on either the EC or G labels. In evaluating the requested revision to the rotational 

crop plant-back restrictions, HED relied on data from field rotational crop studies conducted in 

green bean, lettuce, radish, tomato, and wheat, with plant-back intervals (PBIs) of 30, 60, 120, 

180, 270, and 365 days. For all crop-PBI combinations, residues of fluensulfone were <0.01 

ppm; however, residues of BSA persisted in many crops to 180 days or more, and in wheat 

commodities to at least 365 days. On that basis, HED concluded that the label should prohibit 

rotation to cereal grains and restrict plant-back to 365 days for all other crops not listed on either 

the EC or G labels. 

In addition to the change in PBI, the petitioner requested that the label for the EC formulation be 

amended to allow a maximum application rate of 3.5 lb a.i./A for cucurbit vegetables and fruiting 

vegetables. This was the rate that was originally requested for these crop groups and which was 

used in the field trials submitted to support those uses. As such the data are appropriate for 

establishing tolerances for residues at the requested use rate. As previously noted in Section 2, 

the request for the increased application rate was accompanied by a request to revise the residue 

definition for enforcement to be in terms of the BSA metabolite only (with no stoichiometric 

conversion to parent compound) in order to be harmonized with the definition established by 

Codex. Given the offsetting changes to the tolerance level (increase in residues of 1.4-fold due to 

the rate change and a decrease in residues of 1.5-fold due to the definition change) and the 

rounding classes used by the OECD MRL/tolerance calculation procedures, there is no resulting 

numerical change in the tolerance levels for these to crop groups relative to their currently 

established values.

5.3 Water Residue Profile

Estimates of fluensulfone residues of concern in drinking water were provided by the 

Environmental Fate and Effects Division (EFED) in a memo titled “Fluensulfone: Drinking 

Water Exposure Assessment for Proposed New Uses on Turfgrass” (J. Lin, D424167, 19 

February 2015). The memorandum notes that the estimated drinking water concentrations 

(EDWCs) based on the use on turf are less than those derived from the use on cucurbit 

vegetables and fruiting vegetables. As the use patterns for the new crops are essentially identical 
Fluensulfone D427486

Page 28 of 57

to that for cucurbit and fruiting vegetables, HED has used the cucurbit/fruiting vegetable based 

EDWCs provided by EFED (Table 5.3; J. Lin, D411774, 1 August 2013 and J. Lin, D417634, 30 

January 2013). The EDWCs for groundwater are greater than those for surface water and are

used in the dietary assessment.

Table 5.3. Fluensulfone Estimated Drinking Water Concentrations for Dietary Risk Assessment 

(D411774+D417634).

Residue Source (Tier: Model) Use Rate, 

lb a.i./A/yr

Acute 

EDWC, μg/L

Chronic 

EDWC, μg/L

Surface Water (Tier II: PRZM-EXAMS; D411774; FL 

Cucumber scenario)

3.57 11.8 0.173

Ground water (Tier I: PRZM-GW; D417634; WI Corn 

scenario)

3.57 77.6 52.5

5.4 Dietary Risk Assessment

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments 

were conducted using the Dietary Exposure Evaluation Model software with the Food 

Commodity Intake Database (DEEM-FCID) Version 3.16, which uses 2003-2008 food 

consumption data from the U.S. Department of Agriculture’s National Health and Nutrition 

Examination Survey, What We Eat in America, (NHANES/WWEIA). 

5.4.1 Description of Residue Data Used in Dietary Assessment

Parent fluensulfone occurs at residue levels well below those of BSA, the residue defined for the 

enforcement of tolerances. Since tolerances do not include fluensulfone itself, HED has used the 

OECD MRL calculation procedures to derive tolerance-equivalent residue levels for 

fluensulfone. For foods where the level of fluensulfone is expected to be below the limit of 

quantification (LOQ), 0.01 ppm, HED has assumed that residues occur at the LOQ. For foods 

with quantifiable levels of fluensulfone, HED has assumed that residues occur at the toleranceequivalent level. In addition to the new uses requested for fluensulfone, the dietary assessment 

also addresses the label amendments affecting the previously registered uses for the compound.

5.4.2 Percent Crop Treated Used in Dietary Assessment

HED has assumed that all crops with existing, pending, or requested uses of fluensulfone are 

treated (i.e., 100 percent crop treated).

5.4.3 Acute and Chronic Dietary Risk Assessment

Both the acute and chronic dietary risk assessments are screening-level assessments based on 

tolerance-equivalent residues and 100% crop treated. Generally HED is concerned when risk 

estimates exceed 100% of the acute and/or chronic population-adjusted dose (aPAD/cPAD). For 

fluensulfone, risk estimates are all well below that threshold (Table 5.4.3) and are not of concern. 

As the assessment is based on screening-level assumptions, actual risks from dietary exposure to 

fluensulfone are likely to be less than those provided in the estimates below.
Fluensulfone D427486

Page 29 of 57

Table 5.4.3. Summary of Acute and Chronic Dietary Exposure (Food and Drinking Water) and Risk Estimates for 

Fluensulfone.

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary

Dietary Exposure,

mg/kg/day % aPAD Dietary Exposure,mg/kg/day % cPAD

General U.S. Population 0.004809 3.0 0.001335 1.3

All Infants (<1 year old) 0.014794 9.3 0.003921 3.9

Children 1-2 years old 0.008369 5.2 0.002283 2.3

Children 3-5 years old 0.006513 4.1 0.001811 1.8

Children 6-12 years old 0.004649 2.9 0.001234 1.2

Youth 13-19 years old 0.003774 2.4 0.000943 <1

Adults 20-49 years old 0.004564 2.9 0.001279 1.3

Adults 50-99 years old 0.004165 2.6 0.001297 1.3

Females 13-49 years old 0.004601 2.9 0.001276 1.3

 Bold entries are maximum exposure and risk estimates.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no residential exposure scenarios associated with the petitioned-for uses of 

fluensulfone; however, HED has re-evaluated the available dermal toxicity data and has 

established a new point of departure for this exposure pathway. As a result, new residential risk 

estimates associated with the existing use on turf have been included in this risk assessment.

Residential exposure is expected to be short-term in duration. Intermediate-term exposures are 

not likely because of the intermittent nature of applications by homeowners and the use 

directions (i.e., irrigation following applications in order to get the active ingredient into the root 

zone and soil).

6.1 Residential Handler Exposure

The label recommends the end-use product to be applied by a licensed applicator. Also, the label 

requires handlers to wear PPE (i.e., chemical-resistant gloves). Therefore, a quantitative 

exposure/risk assessment was not developed for residential handlers as the product is not 

intended to be applied by homeowners.

6.2 Post-Application Exposure

All residential post-application assessments assume exposures occur on the same day as 

treatment. The child dermal and incidental oral routes of exposure have been combined as it is 

likely that they can occur simultaneously based on the use pattern and because the toxicological 

effects across these routes of exposure are the same. The individual incidental oral scenarios (i.e., 

hand-to-mouth, object-to-mouth, and soil ingestion) are considered to be inter-related, and it is 

likely that they occur interspersed amongst each other across time. Combining these scenarios 

with the dermal exposure scenario would be overly conservative because of the conservative 

nature of each individual assessment. Assessment of episodic ingestion of granules by children 

resulted in an MOE of 40 (LOC=100). The episodic oral ingestion of granules is listed only as a 

poisoning scenario, and its likelihood is diminished because the label instructs users to irrigate 
Fluensulfone D427486

Page 30 of 57

(i.e., “water-in”) treated areas following applications in order to get the product into the root 

zone and soil.

Table 6.2. Residential Post-application Non-cancer Exposure and Risk Estimates for Fluensulfone.

Lifestage

Post-application Exposure Scenario Application 

Rate, 

lb ai/A (1

Dose,

mg/kg/day (2 MOEs(3

Combined Routes

(X indicates 

included in 

Combined MOE)

Combined 

MOE (4 Use Site Route of Exposure

Adult

Turf (High Contact 

Activities) Dermal 1.8 0.00039 24,000 N/A

Turf (Mowing Turf) Dermal 1.8 0.0000072 1,300,000 N/A

Turf (Golfing) Dermal 1.8 0.0000270 350,000 N/A

Youth 11 < 16 

old years old

Turf (Mowing Turf) Dermal 1.8 0.0000082 1,200,000 N/A

Turf (Golfing) Dermal 1.8 0.0000320 300,000 N/A

Children 6 < 

11 years old Turf (Golfing) Dermal 1.8 0.0000378 250,000 N/A

Child 1 < 2 

years old

Turf (High Contact 

Activities)

Dermal 1.8 0.0007695 12,000 X

11,000

Hand-to-Mouth 1.8 0.0000747 130,000 X

Object-to-Mouth 1.8 0.0000046 2,100,000

Soil Ingestion 1.8 0.0000610 160,000

Episodic Granule

Ingestion 1.8 0.41 40

1. Based on proposed label (EPA Reg. No. 53883-GLT).

2. Dose (mg/kg/day) algorithms provided in 2012 Residential SOPs (http://www2.epa.gov/pesticide-science-and-assessing-pesticiderisks/standard-operating-procedures-residential-pesticide).

3. MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day). POD = 9.6 mg/kg/day for dermal and short-term incidental oral exposure, and 16.2 mg/kg/day 

for episodic granule ingestion.

4. Combined MOE = 1 ÷ (1/dermal MOE) + (1/inhalation MOE) + (1/incidental oral MOE), where applicable.

6.3 Residential Risk Estimates for Use in Aggregate Assessment

Although dermal and inhalation exposures both resulted in similar clinical signs (e.g., decrease 

body weight), the inhalation endpoint selected for risk assessment is based on portal-of-entry 

effects since these effects resulted in lower Human Equivalent Concentrations (HECs) than the 

HEC for systemic effects. Therefore, the portal-of-entry HEC is protective of the systemic 

effects and the dermal and inhalation exposure estimates were not combined since the 

toxicological effects are different for these routes of exposure. 

The child dermal and oral routes of exposure have been combined as it is likely that they can 

occur simultaneously based on the use pattern and because the toxicological effects across these 

routes of exposure are the same. 

Table 6.3 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for fluensulfone.

 The recommended residential exposure for use in the adult aggregate assessment reflects 

dermal exposure only from post-application exposure to outdoor turf/lawn applications 

(high contact activities).

 The recommended residential exposure for use in the children 1<2 years old aggregate 

assessment reflects dermal and hand-to-mouth exposures from post-application exposure 

to outdoor turf/lawn applications (high contact activities).
Fluensulfone D427486

Page 31 of 57

Table 6.3. Recommendations for the Residential Exposures for the Fluensulfone Aggregate Assessment.

Lifestage Exposure Scenario Dose, mg/kg/day (1 MOE (2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult Turf (High Contact 

Activities) 0.00039 N/A N/A 0.00039 24,000 N/A N/A 24,000

Child 1 < 2 

years old

Turf (High Contact 

Activities) 0.00077 N/A 0.0000747 0.0008447 12,000 N/A 130,000 11,000

1. Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + inhalation + incidental oral (where 

applicable). Dermal adult dose is from the high contact activities scenario. Child (1<2 years old) dermal and hand-to-mouth doses are from the 

high contact activities scenario. Both scenarios are listed in Table 6.2.

2. MOE = the MOEs associated with the highest residential doses. 

7.0 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk 

Estimates

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 2010 (http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-

0037). The agency has evaluated the SAP report and has developed a Volatilization Screening 

Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!

docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration Review, the agency will utilize 

this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) 

or further analysis is required for fluensulfone.

8.0 Non-Occupational Spray Drift Exposure and Risk Estimates

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods employed for fluensulfone. 

The agency has been working with the Spray Drift Task Force (a task force composed of various 

registrants which was developed as a result of a Data Call-In issued by EPA), EPA Regional 

Offices and State Lead Agencies for pesticide regulation and other parties to develop the best 

spray drift management practices (see the agency’s Spray Drift website for more information). 1 

The agency has also developed a policy on how to appropriately consider spray drift as a 

potential source of exposure in risk assessments for pesticides. The potential for spray drift will 

be quantitatively evaluated for each pesticide during the Registration Review process which 

ensures that all uses for that pesticide will be considered concurrently. The approach is outlined 

in the revised (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs) -

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift. This document outlines the quantification of indirect non-occupational exposure to 

drift.

 

1 Available: http://www2.epa.gov/reducing-pesticide-drift 
Fluensulfone D427486

Page 32 of 57

9.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from dietary sources as well as other sources for which there is reliable information. In an 

aggregate assessment, exposures from relevant sources are added together and compared to 

quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be 

aggregated. When aggregating exposures and risks from various sources, HED considers both 

the route and duration of exposure.

9.1 Acute Aggregate Risk

For fluensulfone, acute aggregate risk estimates are equivalent to the acute dietary risk estimates 

(Section 5.4) and are not of concern.

9.2 Short-Term Aggregate Risk

In assessing short-term aggregate risk, HED has used the residential exposure estimates provided 

in Table 6.3 in combination with the chronic dietary exposure estimates, as an estimate of cooccurring dietary exposure, to derive short-term aggregate exposure estimates.

Table 9.2. Fluensulfone Aggregate Risk Estimates.

Lifestage Exposure Estimate, mg/kg/day (1 MOE (2

Dietary Dietary Residential Total Aggregate

Adult 0.001288 7,500 24,000 5,700

Child 1 < 2 years old 0.002274 4,200 11,000 3,000

1 See Table 5.4.3.

2 Dietary MOE = 9.6 mg/kg/day ÷ Dietary Exposure; Residential Total MOE from Table 6.3;

Aggregate = 1 ÷ (1/MOEDietary + 1/MOEResidential Total)

The residential exposure scenarios are for dermal and/or oral routes of exposure, for which the 

level of concern for MOEs is 100. The aggregate MOEs are greater than 100, indicating that 

short-term aggregate risk estimates are not of concern.

9.3 Intermediate-Term Aggregate Risk

As previously noted, intermediate-term residential exposures are not expected; therefore, 

intermediate-term aggregate risk is not a concern and quantitative estimates were not calculated.

9.4 Chronic Aggregate Risk

For fluensulfone, long-term exposure from non-dietary sources is not expected. Therefore

chronic aggregate risk estimates are equivalent to the chronic dietary risk estimates (Section 5.4) 

and are not of concern.
Fluensulfone D427486

Page 33 of 57

9.5 Cancer Aggregate Risk

Fluensulfone is classified as having “suggestive evidence of carcinogenicity in humans.” The 

RfD is considered to be protective of potential cancer effects. Based on the chronic 

aggregate/dietary risk estimates, cancer risk is not a concern for fluensulfone.

10.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to fluensulfone and any other substances and fluensulfone does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that fluensulfone has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

11.0 Occupational Exposure/Risk Characterization

This assessment addresses occupational exposures and risks associated with the petitioned-for 

new uses of fluensulfone. In addition, due to revisions to the toxicological points of departure, 

this assessment includes re-evaluation of exposures and risks associated with the previously 

registered uses on cucurbit vegetables, fruiting vegetables, and turf.

11.1 Short-Term Handler Risk

HED derived occupational handler risk estimates for the granular formulation of fluensulfone for 

turf, typical-acreage crop (root vegetables) and high-acreage crop (tuberous and corm 

vegetables) scenarios (Table 11.1.1); and for the EC formulation for typical-acreage row crop 

scenarios, which include the cucurbit vegetables and fruiting vegetables from the previous 

registration as well as the new uses for this assessment (Table 11.1.2).

Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational 

handler risk assessments, obtained either from the proposed labels or from HED’s typical 

assumptions used for completing occupational exposure assessments, unless otherwise noted. 

Each assumption and factor is detailed below on an individual basis.

Application Rate: The maximum proposed application rates are 3.5 lb a.i./A (EC) and 3.6 lb 

a.i./A (G), as listed in Table 3.3.

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. 

Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, 

include PHED 1.1, the Agricultural Handler’s Exposure Task Force (AHETF) database, the 
Fluensulfone D427486

Page 34 of 57

Outdoor Residential Exposure Task Force (ORETF) database, or other registrant-submitted 

occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and 

subject to the data protection provisions of FIFRA. The standard values recommended for use in 

predicting handler exposure that are used in this assessment, known as “unit exposures”, are 

outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table2”, 

which, along with additional information on HED policy on use of surrogate data, including 

descriptions of the various sources, can be found at the agency website3.

Area Treated - Ground Equipment: The inputs for area treated, except chemigation, were based 

on information in ExpoSAC Policy 9.1.

 80 acres for groundboom applications on typical acreage field crops; and

 200 acres and 80 acres for tractor-drawn spreader applications on high and typical 

acreage field crops, respectively.

Area Treated – Chemigation: The registrant, ADAMA, has conducted a survey titled “A Survey 

Quantifying the Number of Acres Chemigated per Day using Drip Irrigation in U.S. Farms" to 

determine a representative estimate for acres chemigated per worker per day to refine the default 

HED assumption of 350 acres chemigated per day. HED has reviewed the survey data, 

confirmed the results using the raw data, and found it acceptable to refine the current input 

assumption of 350 acres treated per day for chemigation (D429723, Z. Figueroa, 8 April 2016). 

HED recommends the risk assessment rely on the surveyed distribution of the average number of 

acres chemigated per day. The distribution appeared to be skewed to the right (asymmetrical, i.e., 

fewer observations were reported towards the higher percentile values of the number of acres 

chemigated per day in the distribution), indicating that the upper percentiles are conservative 

estimates of the central tendency of this distribution. A range of risk estimates using the upperend of that distribution (e.g., 90th, 95th, 99th percentile) has been presented to give a useful 

perspective of the range of risk estimates based on the average acres treated with chemigation 

per day. The 90th, 95th, and 99th percentiles correspond to 100, 155, and 440 acres per day,

respectively. HED’s default value of 350 acres treated per day represents approximately the 

98.7th %tile of the average acres per day distribution.

Based on the survey results, focusing on the chemigation use pattern for fluensulfone (i.e., preplant/pre-transplant spray incorporated into soil for the control of nematodes), HED believes that 

the 95th percentile average acreage treated with chemigation per day (i.e., 155 acres chemigated 

per day) serves as a reasonable estimate for risk assessment. HED notes that this finding is 

limited to the specific conditions of this compound (i.e., soil applied for nematode control) and 

risk assessment, and may not be applicable to other compounds or risk assessment scenarios.

Exposure Duration: HED classifies exposures from 1 to 30 days as short-term and exposures 

from 30 days to six months as intermediate-term. Exposure duration is determined by many 

factors, including the exposed population, the use site, the pest pressure triggering the use of the 

pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is 

reasonable to believe that occupational handlers will not apply the same chemical every day for 

 

2 Available: http://www2.epa.gov/sites/production/files/2015-09/documents/handler-exposure-table-2015.pdf

3 Available: http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handlerexposure-data
Fluensulfone D427486

Page 35 of 57

more than a one-month time frame; however, there may be a large agribusiness and/or 

commercial applicators who apply a product over a period of weeks (e.g., completing multiple 

applications for multiple clients within a region). 

Based on the proposed and registered use pattern (i.e., 1-2 applications per year depending on the 

rate), short- and intermediate-term exposures are expected for occupational handlers. In addition, 

the labels suggest rotating the end-use product with nematicides with a different mode of action.

Mitigation/Personal Protective Equipment: Estimates of dermal and inhalation exposure were 

calculated at baseline attire (i.e., long-sleeved shirts, long pants, shoes plus socks) and for 

various levels of PPE (i.e., chemical-resistant gloves, PF5 and PF 10 respirators) as well as 

engineering controls (closed loading). Results are presented for label specified PPE and 

additional PPE as needed to achieve MOEs above the LOC. The fluensulfone product labels 

direct mixers, loaders, applicators and other handlers to wear chemical-resistant gloves in 

addition to the baseline layer of clothing. The Nimitz® 15G label (EPA Reg. No. 66222-EAE) 

also specifies that operators of tractor-drawn spreaders must wear a PF10 respirator. 

Combining Exposures/Risk Estimates

Although some of the toxicological effects for the dermal and inhalation exposure routes were 

similar (e.g., decrease body weight), these exposure routes are not combined in this assessment 

because the inhalation POD is based on portal-of-entry effects.

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

For both formulations, inhalation MOEs are below the level of concern of 300 for many 

scenarios. For the majority of those cases, addition of a PF5 respirator results in MOEs greater 

than 300. For one scenario with the granular formulation (mixer/loader for tractor-drawn 

spreader for high-acreage crops), the addition of a PF10 respirator results in an MOE of 270; 

engineering controls are needed to obtain an MOE greater than 300 for this scenario.

Table 11.1.1. Fluensulfone Occupational Handler Non-Cancer Exposure and Risk Estimates for Granular End-Use Products

(66222-EAE and 53883-GLT).(1

Exposure 

Scenario

(Granular) Crop

Max. 

Applic. 

Rate, (2

lb ai/A

Area 

Treated,

A (3

Dermal Inhalation

Unit Exposure, 

μg/lb ai (4

[Level of PPE]

Dose, 

mg/kg/day (5 MOE (6

Unit Exposure, 

μg/lb ai (4

[Level of PPE]

Dose,

mg/kg/day

(7 MOE (8

Mixer/Loader

Tractor-drawn 

Spreader

Golf Course 1.8 40 8.4

[Baseline]

0.00072 13,000 1.7

[Baseline]

0.00153 270

0.34

[PF5 Respirator]

0.00031 1,300

Sod (Typical 

Application)

1.8 80 8.4

[Baseline]

0.00118 6,700 1.7

[Baseline]

0.00306 130

0.34

[PF5 Respirator]

0.00061 670

Sod (Rescue 

Treatment)

3.6 80 8.4

[Baseline]

0.00287 3,300 1.7

[Baseline]

0.00613 70

0.34

[PF5 Respirator]

0.00122 340

Typical 

Acreage 

Field Crop

3.6 80 6.9

[Single Layer 

+ Gloves]

0.00236 4,100 1.7

[Baseline]

0.00613 66
Fluensulfone D427486

Page 36 of 57

Table 11.1.1. Fluensulfone Occupational Handler Non-Cancer Exposure and Risk Estimates for Granular End-Use Products

(66222-EAE and 53883-GLT).(1

Exposure 

Scenario

(Granular) Crop

Max. 

Applic. 

Rate, (2

lb ai/A

Area 

Treated,

A (3

Dermal Inhalation

Unit Exposure, 

μg/lb ai (4

[Level of PPE]

Dose, 

mg/kg/day (5 MOE (6

Unit Exposure, 

μg/lb ai (4

[Level of PPE]

Dose,

mg/kg/day

(7 MOE (8

0.34

[PF5 Respirator]

0.00122 330

8.6

[Eng. Ctrl.]

0.00295 3,300 0.083

[EC]

0.000299 1,400

High 

Acreage 

Field Crop

3.6 200 6.9

[Single Layer 

+ Gloves]

0.0059 1,600 1.7

[Baseline]

0.0153 27

0.34

[PF5 Respirator]

0.00306 130

0.17

[PF10 Respirator]

0.00153 270

8.6

[Eng. Ctrl.]

0.00735 1,300 0.083

[Eng. Ctrl.]

0.000748 540

Applicator

Tractor-drawn 

Spreader

Golf Course 1.8 40 9.9

[Baseline]

0.00085 11,000 1.2

[Baseline]

0.00108 380

Sod (Typical 

Application)

1.8 80 9.9

[Baseline]

0.0017 5,600 1.2

[Baseline]

0.00216 190

0.24

[PF5 Respirator]

0.00043 950

Sod (Rescue 

Treatment)

3.6 80 9.9

[Baseline]

0.00338 2,800 1.2

[Baseline]

0.00433 100

0.24

[PF5 Respirator]

0.00086 470

Typical 

Acreage 

Field Crop

3.6 80 7.2

[Single Layer 

+ Gloves]

0.00246 3,900 0.12

[PF10 Respirator]

0.000433 940

2

[Eng. Ctrl.]

0.000684 14,000 0.22

[Eng. Ctrl.]

0.000793 510

High 

Acreage 

Field Crop

3.6 80 7.2

[Single Layer 

+ Gloves]

0.00615 1,600 0.12

[PF10 Respirator]

0.00108 380

2

[Eng. Ctrl.]

0.00171 5,600 0.22

[Eng. Ctrl.]

0.00198 210

Loader/Applicator

Belly Grinder Landscaping, 

Turf (lawns, 

athletic 

fields, parks)

1.8 1 10,000

[Baseline]

0.0214 450 62

[Baseline]

0.0014 290

12.4

[PF5 Respirator]

0.000279 1,500

Rotary Spreader Golf Course, 

Landscaping, 

Turf (lawns, 

athletic 

fields, parks)

1.8 5 440

[Baseline]

0.0047 2,000 10

[Baseline]

0.00113 360

1 EPA Registration File Symbol for the end-use product.

2 Based on registered or proposed labels.

3 Exposure Science Advisory Council Policy #9.1 or survey for number of acres treated with chemigation (MRID No. 49700502).

4 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September 2015); Level of mitigation: Baseline, 

PPE (PF5 Respirator).

5 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated Daily 

(A/day) × DAF (%) ÷ BW (kg).

6 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). LOC=100.

7 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated Daily 

(A/day) ÷ BW (kg).

8 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). MOE=300.
Fluensulfone D427486

Page 37 of 57

Table 11.1.2. Occupational Handler Non-Cancer Exposure and Risk Estimates for End-Use Product Fluensulfone 480EC 

(66222-243).1

Exposure 

Scenario

(EC) Crop

Max. 

Applic. 

Rate, 

lb ai/A (2

Area 

Treated, 

A (3

Dermal Inhalation

Unit Exposure, 

μg/lb ai (4

[Level of PPE]

Dose, 

mg/kg/day (5 MOE (6

Unit Exposure,

μg/lb ai (4

[Level of PPE]

Dose, 

mg/kg/day

(7 MOE (8

Mixer/Loader

Groundboom Typical 

Acreage 

Field Crops

3.5 80 37.6

[Single Layer 

+ Gloves]

0.0125 770 0.219

[Baseline]

0.000766 540 

Chemigation Typical 

Acreage 

Field Crops

3.5 440 37.6

[Single Layer 

+ Gloves]

0.0688 140 0.219

[Baseline]

0.00421 97

0.0438

[PF5 Respirator]

0.000844 490

8.6

[Eng. Ctrl.]

0.0157 610 0.083

[Eng. Ctrl.]

0.0016 260

155 37.6

[Single Layer 

+ Gloves]

0.0242 400 0.219

[Baseline]

0.00149 280

0.0438

[PF5 Respirator]

0.000298 1,400

8.6

[Eng. Ctrl.]

0.00555 1,700 0.083

[Eng. Ctrl.]

0.000563 730

100 37.6

[Single Layer 

+ Gloves]

0.0157 610 0.219

[Baseline]

0.000959 430

8.6

[Eng. Ctrl.]

0.00357 2,700 0.083

[Eng. Ctrl.]

0.000364 1,100

Applicator

Groundboom Typical 

Acreage 

Field Crops

3.5 80 16.1

[Single Layer 

+ Gloves]

0.00536 1,800 0.34

[Baseline]

0.00119 340

1 EPA Registration Number for the end-use product.

2 Based on registered or proposed labels.

3 Exposure Science Advisory Council Policy #9.1 or survey for number of acres treated with chemigation (MRID No. 49700502; 100 A=90th

percentile, 155 A=95th percentile, 440 A=99th percentile).

4 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September 2015); Level of mitigation: Baseline, 

PPE (PF5 Respirator).

5 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated Daily 

(A/day) × DAF (%) ÷ BW (kg).

6 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). LOC=100.

7 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated Daily 

(A/day) ÷ BW (kg).

8 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). MOE=300.

11.2 Short-Term Post-Application Risk

HED has evaluated the occupational post-application exposures to fluensulfone for the use on 

typical row crops (both new uses and previously registered uses) as well as the use on turf.

11.2.1 Dermal Post-Application Risk

Row Crops. There is a low potential for occupational post-application exposure associated with 

the use of pre-plant/pre-emergent nematicides because there are no hand labor activities typically 

associated with the production of crops that would require significant contact with treated soil. 

Furthermore, no foliage will be present at time of application that could lead to exposure via 

post-application contact activities. 
Fluensulfone D427486

Page 38 of 57

There is a potential for workers to contact treated soil during mechanically assisted cucurbit and 

fruiting vegetables transplanting activities; however, this event is likely to result in negligible 

exposures because transplanting activities involve moving starter plants onto a rotating wheel 

while riding upon an implement being moved across a field. In such cases, there would be 

minimal contact with machinery, which may carry small amounts of treated soil, because of the 

possibility of mechanical injury. Also, commercial cultivation is typically in tarped, raised beds 

with small planting holes punched in the tops of the raised beds. Even though fluensulfone is 

stable under environmental conditions, the parent compound has approximately a 10-day halflife in field dissipation studies which decreases the potential for occupational exposure to treated 

soil. These considerations for application of fluensulfone to cucurbit and fruiting vegetables

support HED’s conclusion that dermal post-application exposure is negligible, and therefore a 

quantitative dermal post-application exposure assessment was not conducted.

Sod and Turf. A summary of the post-application dermal exposure and risk estimates from use of 

fluensulfone on treated sod/turf is provided in Table 11.2.1. Post-application dermal exposure 

estimates reflect turf transferrable residues from Day 0 after treatment and resulted in MOEs 

greater than 100 and are not of concern. Estimated exposure could be much lower (i.e., MOEs 

much higher) due to the label recommendation to irrigate turf immediately after application for 

most effective nematode control.

Table 11.2.1. Occupational Short-Term, Post-Application, Non-Cancer, Dermal Exposure and Risk Estimates for 

Fluensulfone from use on Sod and Turf.

Crop/Site Activities Transfer Coefficient,

cm2/hr TTR (1 Dermal Dose,mg/kg/day (2 MOE (3

Sod Farm 

(Rescue Treatment) Maintenance, Harvesting, Slab 

Transplanting/Planting 6,700

0.0022 0.000127 24,000

Sod Farm/Turf 

(Typical Application) 0.0011 0.000064 49,000

Golf Course Maintenance (greens only) 2,500 0.0011 0.000024 130,000

Maintenance 3,700 0.0011 0.000035 88,000

1. Predicted TTR at initial concentration (t0) = 0.0022 ug/cm2at 3.6 lb ai/A or 0.0011 ug/cm2at 1.8 lb ai/A from chemical-specific study (EPA 

MRID No. 49552503).

2. Daily Dermal Dose = [TTR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (9.5%)]  BW (80 kg).

3. MOE = POD (mg/kg/day) / Daily Dermal Dose. LOC=100.

Restricted Entry Interval

Fluensulfone is classified as Toxicity Category III via the dermal route and Toxicity Category IV 

for skin and eye irritation potential. The EC formulation is a skin sensitizer, however the 

granular formulation is not. Since a quantitative dermal post-application exposure assessment 

was not conducted, the REI specified on the registered label is based on the acute toxicity of 

fluensulfone. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute III or IV 

for acute dermal, eye irritation and primary skin irritation are assigned a 12-hour REI. Therefore, 

the [156 subpart K] Worker Protection Statement interim REI of 12 hours should be listed on the 

proposed and registered labels in order to protect agricultural workers from post-application 

exposures to fluensulfone.
Fluensulfone D427486

Page 39 of 57

11.2.2 Inhalation Post-Application Risk

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-0037). The agency 

has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for fluensulfone.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the agency's risk assessments.

12.0 References

Cowins, J. 29 April 2016. D427502. Fluensulfone. Petition from ADAMA Agricultural

Solutions, Ltd. (formerly Makhteshim Agan of North America, Inc.), and IR-4 for 

Registration of Uses on Crop Subgroup 1B, Crop Subgroup 1C, Crop Group 4, Crop 

Group 5, Crop Subgroup 13-07G, and Tobacco, Establishment of Associated Tolerances, 

and Label Amendments to Revise the Rotational Crop Plant-Back Restriction and 

Increase the Application Rate for Crop Groups 8-10 and 9. Summary of Analytical 

Chemistry and Residue Data.

Cowins, J. 29 March 2016. D432134. Fluensulfone Acute and Chronic Aggregate Dietary 

(Food and Drinking Water) Exposure and Risk Assessments for the New Use Section 3 

Registration Action on Root Vegetables (Except Sugar Beet), Tuberous and Corm 

Vegetables, Leafy Vegetables (Except Brassica Vegetables), Brassica (Cole) Leafy 

Vegetables, Fruiting and Cucurbit Vegetables, and Low growing berry Crop 

Groups/Subgroups.

Doherty, M., D’Agostino, J., and Figueroa, Z. 18 June 2014. D403767. Fluensulfone: New 

Active Ingredient Human Health Risk Assessment of Proposed Uses on Cucurbit 

Vegetables and Fruiting Vegetables.

Doherty, M., D’Agostino, J., and Figueroa, Z. 6 January 2015. D424168. Fluensulfone: 

Human Health Risk Assessment of the Proposed Use on Turf.

Figueroa, Z. 12 April 2016. D432885. Fluensulfone. Updated Occupational and Residential 

Exposure Assessment for the Uses on Golf Courses, Sports Fields, Commercial Areas, 

Sod Farms, and Residential Turfgrass/Lawns and Cucurbits and Fruiting Vegetables.
Fluensulfone D427486

Page 40 of 57

Figueroa, Z. 12 April 2016. D429723. Fluensulfone. Review of the Study: “A Survey 

Quantifying the Number of Acres Chemigated per Day using Drip Irrigation in U.S. 

Farms” sponsored by Makhteshim Agan of North America D/B/A ADAMA. MRID No. 

49700502.

Lin, J. 1 August 2013. D411774. Fluensulfone: Drinking Water Exposure Assessment for 

Proposed New Registration for uses on cucurbits and fruiting vegetables.

Lin, J. 20 January 2014. D417634. Fluensulfone: Refined Drinking Water Exposure 

Assessment for Proposed New Registration for Uses on Cucurbits and Fruiting 

Vegetables Based on Ground Water Sources.

Lin, J. 20 October 2015. D428910. Fluensulfone: Drinking Water Exposure Assessment for 

Proposed New Uses on Tuberous and Corm Subgroup 1C, Brassica (Crop Group 5A and 

5B), Leafy Vegetables (Crop Group 4), Root Vegetables (Crop Group 1B), Strawberry 

including low growing berry subgroup (Crop Group 13-07G), and Tobacco

Thornton, G. 12 April 2016. D431914. Fluensulfone. Occupational and Residential Exposure 

Assessment for a Proposed Use on Brassica subgroup 5A and 5B, Leafy vegetables group 

4, Low growing berry subgroup 13-07G, Tobacco, Root vegetables 1B (including leafy 

portions), and Tuberous and corm vegetables 1C.

U.S.EPA. 1991. Alpha2u-Globulin: Association with Chemically Induced Renal Toxicity and 

Neoplasia in the Male Rat. U.S. Environmental Protection Agency, Risk Assessment 

Forum, Washington, DC, EPA/625/3-91/019F (NTIS PB92143668), 1991.
Fluensulfone D427486

Page 41 of 57

Attachment 1. Fluensulfone bibliography to support label amendments and new uses.

MRID Study Author Title

49553604 Everich, R. Fluensulfone: Waiver Request for Residue Chemistry Guideline OPPTS 860.1480 

Meat/Milk/Poultry/Eggs

49553607 Polakoff, B. Fluensulfone: Fulfillment of the Residue Data Requirements in Support of 

Tobacco Use

49553608 Jones, G. Magnitude of the Residue of MCW-2 in Strawberries

49553609 Jones, G. Magnitude of the Residue of MCW-2 in Tobacco

49553610 Jones, G. Magnitude of the Residue of MCW-2 in Radish

49553611 Jones, G. Magnitude of the Residue of MCW-2 in Japanese Leafy Vegetables

49553612 Jones, G. Magnitude of the Residue of MCW-2 in Japanese Root Vegetables

49553613 Lennon, G. Magnitude of the Residue on Carrot

49553614 Jones, G. Magnitude of the Residue of MCW-2 in Brassica Vegetables

49553618 Jones, G. Magnitude of the Residue of MCW-2 in Leafy Vegetables

49643601 Lennon, G. Fluensulfone: Magnitude of the Residue on Potato

49709701 Jones, G. Magnitude of the Residue of Fluensulfone and Its Metabolites in Rotational Crops 

under Field Conditions

49552503 Riley, M. Determination of Transferable Residues of Fluensulfone on Turf Treated with 

MCW-2 1.5% GR Nematicide

49700502 Thompson, R. A Survey Quantifying the Number of Acres Chemigated per Day Using Drip 

Irrigation in U.S. Farms
Fluensulfone D427486

Page 42 of 57

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for fluensulfone are below. Use of the new guideline numbers does not imply 

that the new (1998) guideline protocols were used.

Test Technical Fluensulfone

Required Satisfied

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Primary Eye Irritation

870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

870.3150 Oral Subchronic (nonrodent)

870.3200 21/28-Day Dermal

870.3250 90-Day Dermal

870.3465 90-Day Inhalation

yes

yes

yes

no

yes

yes

yes

yes

-

yes

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (nonrodent)

870.3800 Reproduction

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial

870.5300 Mutagenicity—Gene Mutation - mammalian

870.5375 Mutagenicity—Structural Chromosomal Aberrations

870.5550 Mutagenicity—Other Genotoxic Effects

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

870.6100b 90-Day Neurotoxicity (hen)

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90-Day Neurotoxicity Screening Battery (rat)

870.6300 Developmental Neurotoxicity

no

no

yes

yes

no

--

--

yes

yes

--

870.7485 General Metabolism

870.7600 Dermal Penetration

870.7800 Immunotoxicity

yes

yes

yes

yes

yes

yes
Fluensulfone D427486

Page 43 of 57

A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile - Fluensulfone technical 

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral - rat 48574745 LD50 = 671 III

870.1100 Acute oral - rat 48574746 LD50 > 300 mg/kg 

but < 2000 mg/kg

III

870.1200 Acute dermal - rat 48575035 LD50 > 2000 mg/kg III

870.1300 Acute inhalation - rat 48574748 LC50 > 5.1 mg/L IV

870.2400 Acute eye irritation - rabbit 48574750 Non-irritant IV

870.2500 Acute dermal irritation - rabbit 48574749 Non-irritant IV

870.2600 Skin sensitization - guinea pig 48574751 Sensitizer N/A

Table A.2.2. Acute Toxicity Profile - Fluensulfone granular formulations

Guideline No.

Study Type MRID(s) Results (from study 

report)

Toxicity Category

870.1100 Acute oral – rat, 15GR 49488603 LD50 > 2000 mg/kg III

870.1100 Acute oral – rat, 1.5GR 49488608 LD50 > 2000 mg/kg III

870.1200 Acute dermal – rat, 15GR 49488604 LD50 > 2000 mg/kg III

870.1300 Acute inhalation - rat waived - -

870.2400 Acute eye irritation – rabbit, 15GR 49488605 Non-irritant IV

870.2500 Acute dermal irritation – rabbit, 

15GR

49488606 Slightly irritating IV

870.2600 Skin sensitization – mice, 15GR 49488607 Not a sensitizer N/A

Table A.2.3. Acute Oral Toxicity Profile - Fluensulfone Metabolites

Metabolite Study Type MRID(s) Results Toxicity Category

TSA Acute oral - rat 48574783 LD50 > 2000 mg/kg III

MeS Acute oral - rat 48574787 LD50 > 300 mg/kg 

but < 2000 mg/kg

II

BSA Acute oral - rat 48574792 LC50 > 2000 mg/kg III

Table A.2.4. Toxicity Profile - Fluensulfone 

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

870.3100 2003-90-day 

dietary-rat

mg/kg/day =

M: 0, 4.3, 8.3, 34.9, 139.0

F: 0, 4.8, 11.7, 53.1, 148.7

Acceptable/Guideline

48575035 NOAEL (mg/kg/day): 

M=8.3, F=11.7

LOAEL (mg/kg/day): M=34.9, F=53.1 

based on kidney effects, observations in the 

pharynx and forestomach, increased 

cholesterol in females, and decreased body 

weight and body weight gain in males. 

870.3100 2002-28-day 

dietary-rat 

mg/kg/day=

M: 0, 10.4, 42.5, 152.0

F: 0, 12.2, 37.2, 165.9

Acceptable/Guideline

48575023 NOAEL (mg/kg/day): 

M=10.4, F=12.2

LOAEL (mg/kg/day):

M=42.5, F=37.2 based on decreased body 

weight gain in both sexes, increased WBC 

in females, increased cholesterol in males 
Fluensulfone D427486

Page 44 of 57

Table A.2.4. Toxicity Profile - Fluensulfone 

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

and renal pathology in males.

870.3100 2003-90-day 

dietary-mouse

mg/kg/day =

M: 0, 11, 51, 228

F: 0, 18, 68, 252

Acceptable/Guideline

48574753 NOAEL (mg/kg/day): 

M=11, F=18

LOAEL (mg/kg/day): 

M=51, F=68 based on increased bilirubin, 

hematology effects in males, and reduced 

food consumption in females.

870.3100 2003-28-day 

dietary-mouse

mg/kg/day =

M: 0, 30, 101, 375

F: 0, 41, 155, 353

Acceptable/Guideline

48575024 NOAEL (mg/kg/day): 

M=30, F=41

LOAEL (mg/kg/day): 

M=101, F=155 based on decreased food 

consumption, decreased platelets in males, 

decreased absolute heart weight in males, 

and increased relative liver weight in 

females.

870.3150 2002-90-day 

dietary-dog 

mg/kg/day =

M: 0, 0.2, 1.6, 17.1

F: 0, 0.2, 1.8, 18.0

Acceptable/Guideline

48574755 NOAEL (mg/kg/day): 

M=1.6, F= 1.8

LOAEL (mg/kg/day): M=17.1, F=18.0

based on decreased plasma and liver 

ALAT, liver effects, hematological 

findings, altered clinical chemistry, 

increased TSH, decreased body weight 

gains and decreased body weight in 

females.

870.3150 2002-28-day 

dietary-dog 

mg/kg/day =

M: 0, 1.9, 7.3, 31

F: 0, 2.0, 7.9, 30

Acceptable/Guideline

48574752 NOAEL (mg/kg/day): 

M=7.3, F= 7.9

LOAEL (mg/kg/day): M=31, F=30

based on slight decreases in body weight 

and slight increases in liver and thyroid 

weight.

870.3200 2011-28-day 

dermal-rat

mg/kg/day =

0, 80, 400, 2000

Acceptable/Guideline

48574758 Systemic: NOAEL (mg/kg/day):

400

LOAEL (mg/kg/day): 2000 based reduced 

body weight gain, increased prothrombin 

time and increased relative spleen weight in 

males; increased reticulocytes and 

increased cholesterol in females.

870.3465 2012-90-day 

inhalation-rat

mg/L/day =

0, 0.04, 0.2, 1.0

Acceptable/Guideline

48575045 NOAEL (mg/L/day):

Not determined

LOAEL (mg/kg/day): 

0.04 based on weight loss in males, 

prolonged prothrombin time in females, 

decreased thymus weight in males, 

histopathological changes in the epiglottis 

in both sexes, and histopathological 

changes in the nasal cavity of males.

870.3700 2003-

developmental 

tox-rat

mg/kg/day =

0, 8, 50, 300

Acceptable/Guideline

48574771 Maternal: NOAEL (mg/kg/day): 50

LOAEL (mg/kg/day): 300 based on 

decreased body weight and food 

consumption.
Fluensulfone D427486

Page 45 of 57

Table A.2.4. Toxicity Profile - Fluensulfone 

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

Developmental: NOAEL (mg/kg/day): 50

LOAEL (mg/kg/day): 300 based on 

decreased body weight.

870.3700 2009-

developmental 

tox-rabbit

mg/kg/day =

0, 2.5, 10, 40

Acceptable/Guideline

48574770 Maternal: NOAEL (mg/kg/day): 10 

LOAEL (mg/kg/day): 40 based on transient 

weight loss and decreased food 

consumption, GD6-9.

Supported by significant toxicity at 50 

mg/kg/day (marked body weight loss, cold 

ears, decreased food intake, and discolored 

urine) observed in the range finding study.

Developmental: NOAEL (mg/kg/day): 10

LOAEL (mg/kg/day): 40 based on reduced 

body weight and incomplete ossification of 

digit 5 of the medial phalanx in both 

forelimbs.

870.3800 2011-2-

generation 

reproductionrat

mg/kg/day =

P, male: 0,1.9, 15.4, 114.2, 

P, female: 0, 2.7, 22.8, 

164.8

F1, male: 0, 2.0, 17.0, 

129.7

F1, female: 0, 2.9, 23.3, 

169.1

Acceptable/Guideline

48574769 Parental: 

NOAEL (mg/kg/day):

M=16.2, F=23.0 

LOAEL (mg/kg/day):

M=122.0, F=169.1 based on decreased 

body weight

Reproductive:

NOAEL (mg/kg/day):

M=16.2, F=23.0 

LOAEL (mg/kg/day): M=122.0, F=169.1 

based on an increase in post-natal pup loss 

in both P and F1 generations.

Offspring: 

NOAEL (mg/kg/day):

M=16.2, F=23.0 

LOAEL (mg/kg/day): M=122.0, F=169.1 

based on decreased pup and spleen weights.

870.4100 2011-1-year 

dietary-dog

mg/kg/day =

M: 0, 0.1, 1.5, 3.1, 16.0

F: 0, 0.1, 1.5, 3.3, 16.2

Acceptable/Guideline

48574756 NOAEL (mg/kg/day): 

M=3.1, F= 3.3

LOAEL (mg/kg/day): M=16.0, F=16.2 M: 

based on decreased body weight and 

changes in hematological and clinical 

chemistry parameters in both sexes.

870.4200 2011-18-month 

carcinogenicity

-mouse

mg/kg/day =

M: 0, 4.2, 27.6, 152.3

F: 0, 6.4, 39.0, 188.4

Acceptable/Guideline

48574766 NOAEL (mg/kg/day):

M=4.2, F=6.4

LOAEL (mg/kg/day):

M=27.6, F=39.0 based on an increased 

incidence of lung bronchiolization and 

decreased body weight and body weight 

gain in males.

Increased incidence of lung adenomas 
Fluensulfone D427486

Page 46 of 57

Table A.2.4. Toxicity Profile - Fluensulfone 

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

above historical controls was observed in 

females; combined adenoma/carcinomas 

was also increased (carcinoma only 

increased trend).

870.4300 2011-2-year 

toxicity/carcino

genicity-rat

mg/kg/day =

Oncogenicity group

M: 0, 1.4, 9.6, 57.7

F: 0, 1.7, 11.6, 69.3

Chronic toxicity group

M: 0, 1.6, 11.0, 66.3

F: 0, 1.9, 13.1, 75.2

Acceptable/Guideline

48574765 NOAEL (mg/kg/day):

M=9.6, F=11.6

LOAEL (mg/kg/day): 

M=57.7, F=69.3 based on decreased body 

weight in males, and hematology and 

clinical chemistry findings and 

histopathological changes in the lungs and 

esophagus in both sexes.

870.5100 2002-Bacterial 

reverse 

mutation assay 

(MCW-2)

Test 1: 0, 16, 50, 158, 500, 

1581, or 5000 g/plate 

(Salmonella typhimurium) 

in the presence and 

absence of metabolic 

activation (+ S9).

Test 2: 0, 1000, 2000, 

3000, 4000, 5000, or 6000

g/plate (Salmonella 

typhimurium) in the 

presence and absence of 

metabolic activation (+

S9).

Test 3: 0, 375, 750, 1300, 

2600, or 5200 g/plate 

(Salmonella typhimurium) 

in the absence of 

metabolic activation (-S9).

Acceptable/Guideline

48574759/

48575015

Negative with strains TA1535, TA1537, 

TA98, and TA102.

Weakly positive with strain TA 100.

870.5100 2008-Bacterial 

reverse 

mutation assay 

(MCW-2)

Test 1: 0, 3, 10, 33, 100, 

333, 1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Test 2: 0, 33, 100, 333, 

1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

48574760 Negative 
Fluensulfone D427486

Page 47 of 57

Table A.2.4. Toxicity Profile - Fluensulfone 

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

Acceptable/Guideline

870.5100 2011-Bacterial 

reverse 

mutation assay 

(MCW-2)

Test 1: 0, 10, 32, 100, 316, 

1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Test 2: 0, 3, 10, 32, 100, 

316, 1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Acceptable/Guideline

48574761 Negative 

870.5100 2010-Bacterial 

reverse 

mutation assay 

(MCW-2 

metabolite 

#3625)

Test 1: 0, 3, 10, 33, 100, 

333, 1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Test 2: 0, 33, 100, 333, 

1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Acceptable/Guideline

48574784 Negative

870.5100 2010-Bacterial 

reverse 

mutation assay 

(MCW-2 

metabolite 

#3626)

Test 1: 0, 3, 10, 33, 100, 

333, 1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Test 2: 0, 33, 100, 333, 

1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Test 3: 0, 100, 333, 1000, 

2500, 3750, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

48574788 Negative, except positive with Salmonella 

typhimurium strain TA100 in the absence 

of metabolic activation
Fluensulfone D427486

Page 48 of 57

Table A.2.4. Toxicity Profile - Fluensulfone 

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

absence of metabolic 

activation (+ S9).

Acceptable/Guideline

870.5100 2010-Bacterial 

reverse 

mutation assay 

(MCW-2 

metabolite 

#3627)

Test 1: 0, 3, 10, 33, 100, 

333, 1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Test 2: 0, 33, 100, 333, 

1000, 2500, or 5000

g/plate (Salmonella 

typhimurium-Escherichia 

coli) in the presence and 

absence of metabolic 

activation (+ S9).

Acceptable/Guideline

48574793 Negative

870.5300 2003-In vitro

mammalian cell 

gene mutation 

assay (MCW-2)

Without activation: 0, 24, 

32, 40, 48, 56, 64, 72 

g/ml

With activation: 0, 20, 30, 

40, 50, 60, 70, 80 g/ml

Acceptable/Guideline

48574763 Negative

870.5300 2011-In vitro

mammalian cell 

gene mutation 

assay (MCW-2 

metabolite 

#3626)

Without activation: test1 = 

0, 3.8, 7.5, 15, 30, 40, 50, 

60 g/ml, test 2 = 0, 5.5, 

10.9, 21.9, 43.8, 87.5, 

131.3, 175 g/ml

With activation: test 1 = 0, 

37.5, 75, 150, 300, 600, 

800, 1000 g/ml, test 2 = 

0, 87.5, 175, 350, 700, 

800, 900, 1000 g/ml

Acceptable/Guideline

48574789 Negative

870.5375 2010-In vitro

mammalian cell 

chromosome 

aberration test 

(MCW-2)

0, 62.5, 125, 250, 500, 

1000 μg/mL with and 

without metabolic 

activation 

Acceptable/Guideline

48574762 Negative

870.5375 2010-In vitro

mammalian cell 

chromosome 

aberration test 

(MCW-2 

Test 1: 0, 9.3, 18.5, 37, 

74.1, 148.1, 296.3, 592.5, 

1185, 2370 μg/mL with 

and without metabolic 

activation 

48574785 Negative
Fluensulfone D427486

Page 49 of 57

Table A.2.4. Toxicity Profile - Fluensulfone 

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

metabolite 

#3625) Test 2: 0, 9.3, 18.5, 37, 

74.1, 148.1, 296.3, 592.5, 

1185, 2370 μg/mL without 

metabolic activation and 

148.1, 296.3, 592.5, 1185, 

2370 μg/mL with 

metabolic activation

Acceptable/Guideline

870.5375 2010-In vitro

mammalian cell 

chromosome 

aberration test 

(MCW-2 

metabolite 

#3627)

Test 1: 0, 8.3, 16.6, 33.3, 

66.6, 133.2, 266.4, 532.8, 

1065.5, 2131 μg/mL with 

and without metabolic 

activation 

Test 2: 0, 8.3, 16.6, 33.3, 

66.6, 133.2, 266.4, 532.8, 

1065.5, 2131 μg/mL 

without metabolic 

activation and 133.2, 

266.4, 532.8, 1065.5, 2131 

μg/mL with metabolic 

activation

Acceptable/Guideline

48574794 Negative

870.5395 2003-

mammalian 

erythrocyte 

micronucleus 

test (MCW-2)

mg/kg/day = 0, 75, 150, 

300

Acceptable/Guideline

48574764 Negative

870.5395 2011-

mammalian 

erythrocyte 

micronucleus 

test (MCW-2 

metabolite 

#3625)

mg/kg/day = 0, 500, 

1000, 2000

Acceptable/Guideline

48574786 Negative

870.5395 2011-

mammalian 

erythrocyte 

micronucleus 

test (MCW-2 

metabolite 

#3626)

mg/kg/day = 0, 125, 250, 

500

Acceptable/Guideline

48574791 Negative

870.5395 2010-

mammalian 

erythrocyte 

micronucleus 

test (MCW-2 

metabolite 

#3627)

mg/kg/day = 0, 500, 

1000, 2000

Acceptable/Guideline

48574795 Negative
Fluensulfone D427486

Page 50 of 57

Table A.2.4. Toxicity Profile - Fluensulfone 

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

870.5550 2011-

unscheduled 

DNA synthesis 

(MCW-2 

metabolite 

#3626)

mg/kg/day = 0, 250, 500

Acceptable/Guideline

48574790 Negative

870.6200 2010-Acute 

neurotoxicityrat

mg/kg/day = 0, 100, 400, 

1200

Acceptable/Guideline

48574773 NOAEL (mg/kg/day): not identified

LOAEL (mg/kg/day): 100 based on 

decreased spontaneous activity, decreased 

rearing, impaired righting response, and 

reduced locomotor activity in females.

870.6200 2011-90-day 

neurotoxicityrat

mg/kg/day =

M: 0, 6, 31, 153

F: 0, 7, 34, 162

Acceptable/Guideline

48574774 NOAEL (mg/kg/day): M=31, F=34

LOAEL (mg/kg/day): M=153, F=162 based 

on decreased food consumption, decreased 

body weight gain, and decreased body 

weight in males.

870.7485 2011-

Metabolism 

and excretion, 

single oral-rat 

([thiazole14C]MCW-2 

and [butene14C]MCW-2)

mg/kg/day =

5 and 500 

Acceptable/Guideline

48574742 The recovery of radioactivity was 91.3-

97.3% of the administered dose for all 

groups of rats. The disposition and 

excretion of radiolabel for males and 

females were generally similar. Urine was 

the major route of excretion for both 

radiolabel positions; 75-88% of the 

administered dose was excreted in urine 

depending on the dosing. Unmetabolized 

fluensulfone was not detected as a 

significant residue in either urine or feces. 

The study investigators indicated that 

initially the parent compound probably 

reacts with glutathione to displace butene 

sulfinic acid, the major urinary metabolite. 

870.7485 2011-

Metabolism 

and excretion, 

repeat oral-rat (

[butene14C]MCW-2)

mg/kg/day =

5 

Acceptable/Guideline

48574744 The recovery of excreted radiolabel was 

94-99% for individual rats. Radiolabel was 

found mainly in urine (71-83%), feces (9-

11%) and the cage wash (6-16%). One day 

after dosing with radiolabeled fluensulfone, 

an average of 0.6-0.8% of the administered 

radiolabel was in liver and 0.1% in kidney 

with 1.7-2.1% in the carcass (selected 

tissues removed) and 4.5-4.7% remained in 

the gastro-intestinal tract. By 7 days after 

treatment with radiolabeled fluensulfone, 

an average of 0.1-0.2% of the administered 

radiolabel remained in liver and 0.03% in 

kidney. There were no significant sex 

differences in either elimination or tissue 

residues. Analysis of urine showed four 

major metabolites identified as thiazole 

sulfonic acid (TSA), glucuronide I, 

glucuronide II and thiazole mercapturate.

870.7485 2010-

pharmacokineti

mg/kg/day =

5 and 500

48574741 The absorption of fluensulfone-derived 14C 

was rapid at both doses. The kinetic 
Fluensulfone D427486

Page 51 of 57

Table A.2.4. Toxicity Profile - Fluensulfone 

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

cs, single oralrat ([thiazole14C]MCW-2 

and [butene14C]MCW-2)

Acceptable/Guideline

parameters for males and females were 

generally similar for the butene radiolabel, 

while for the thiazole label, male rats 

demonstrated a slightly higher absorption 

based on AUC values in whole blood. 

Fluensulfone reacts with the free thiol 

moiety of globin (protein of hemoglobin) to 

form a covalent linkage to the thiazole 

group and displaces butene sulfinic acid.

870.7485 2011-

toxicokinetic 

study-rat 

([thiazole14C]MCW-2 

and [butene14C]MCW-2)

mg/kg/day =

5 and 500

Acceptable/Guideline

48574743 Residues were generally similar between 

males and females. For both labels and both 

dose levels, the gastrointestinal tract, liver 

and kidney were among the tissues 

containing the highest radioactivity levels 

at Cmax for both sexes. As predicted by the 

pharmacokinetic study, radioactivity from 

the thiazole label was slowly eliminated 

from red blood cells consistent with the 

derivatization of the hemoglobin cysteine 

thiol. The ratio of residues at the Cmax

compared to the DT90 was near the 

expected 10% for plasma, but for the 

thiazole label (low and high doses) was 

>25% for numerous tissues/organs. For the 

butene label (low and high doses), the ratio 

of residues at Cmax compared to DT90 was 

also >25% for numerous tissues/organs

except those involved with the digestive 

system. The slow elimination of 

radioactivity with the thiazole and butene 

labels may reflect metabolism of [14C]

fluensulfone to 1- and 2-carbon fragments 

with reincorporation in natural products 

(e.g. protein, fatty acids) with long turnover 

rates.

870.7600 2011 Dermal 

penetration in 

vivo – male rat

Mg/cm2 = 0.1 (label 

dilution of commercial 

formulation) and 4.8 

(undiluted commercial 

formulation) 480 EC 

formulation; equivalent to 

10 g a.i./L and 480 g 

a.i./L, respectively. All 

animals exposed for 10 

hours, then monitored at 

24, 72 or 120 hrs.

48574949 MCW-2 as the MCW-2 480 EC 

formulation penetrated rat skin at both high 

and low dose levels at a relatively high 

level (63.71 and 19.16% AD at 10 hours, 

respectively), which was mainly excreted in 

the urine. The maximum potentially 

absorbable % AD for the low and high dose 

groups is 64% at 10 hrs and 21% at 24 h, 

respectively. After five days, 2.2% of low 

dose and 0.66% of high dose radioactivity 

remained in the animals. The calculated 

penetration rates did not increase in a 

proportional fashion with dose.

870.7800 2011-28-day 

immunotoxicity

-mice

mg/kg/day =

0, 17, 86, 204

Acceptable/Guideline

48574779 Systemic: NOAEL (mg/kg/day):

86

LOAEL (mg/kg/day): 204 based on 

mortality, clinical signs and decreased body 
Fluensulfone D427486

Page 52 of 57

Table A.2.4. Toxicity Profile - Fluensulfone 

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

weight and food consumption.

Immunotoxicity: NOAEL (mg/kg/day):

204

LOAEL (mg/kg/day):

not determined

Special 

study

2011 – 3 or 7-

day dietary 

study 

evaluating 

BrdU 

incorporation in 

lungs – female 

mice

0 or 1200 ppm

Acceptable/nonguideline

48574767 At 1200 ppm increased cell proliferation 

was observed in the lungs as determined by 

BrdU incorporation. The effect was 

transient, observed at 3 days but not after 7 

days.

Special 

study

2011 –

Comparative 

biotransformati

on in human vs. 

mouse lung 

microsomes

2 or 20 μM, in vitro

incubation 

Acceptable/nonguideline

48574768 Fluensulfone was extensively metabolized 

by mouse lung microsomes but not by 

human lung microsomes. Mouse Cyp2f2 

appeared to be involved in the metabolism.

Special 

study

2009 –

Inhibition of 

Alanineaminotransferas

e (ALAT) in a 

28-day dog 

dietary study

0, 50, 200 or 900 ppm

Acceptable/nonguideline

48574775 Liver, serum and liver cytosolic fractions of 

untreated dogs, spiked with serum or 

cytosolic fractions from fluensulfonetreated dogs, did not show inhibition of 

ALAT activity in the untreated dogs. The 

decrease in ALAT activity was therefore 

not likely to be due to direct inhibition of 

the enzyme by fluensulfone/ metabolites, or 

inhibition of the ALAT gene or protein 

expression in the liver.

Special 

study

2011 – 2-week 

dietary study in 

dog –

evaluation of 

MOA for 

decreased 

ALAT activity

0 or 500 ppm

Acceptable/nonguideline

48574776 Reduced ALAT activity was not due to 

decreased mRNA or protein expression, or 

decreased cofactor pyridoxal 5’-phosphate.

Special 

study

2010 – in vitro

inhibition of 

ALAT activity 

by fluensulfone 

from liver 

microsomes of 

untreated dogs

Up to approximately 19.1 

μM, in vitro incubation

Acceptable/nonguideline

48574777 Fluensulfone did not cause a direct 

inhibition of ALAT activity when 

incubated with dog liver homogenates.

Special 

study

2009 –

Determination 

of hepatic 

ALAT in 

untreated dogs

Untreated animals 48574778 An historical database for adult male and 

female beagle dogs was established based 

on data collected between 6/09 and 9/09

Special 

Study

2011-

comparative in 

vitro dermal 

mg/cm2 =

0.1 and 4.8 480 EC 

formulation.

48574950 The total absorption was calculated to be 

92.11% and 81.26% (low and high dose), 

and 62.46% and 4.65% (low and high dose) 
Fluensulfone D427486

Page 53 of 57

Table A.2.4. Toxicity Profile - Fluensulfone 

Guideline Study Type Doses Tested/Study 

Classification

MRID Results

absorption 

(MCW-2 

[Ring-U14C])

Acceptable/nonguideline

for rat and human skin membranes, 

respectively. Based on percentages 

absorbed, the ratio between human and rat 

skin membrane was 1:1.5 for the low dose 

level and 1:18 for the high dose level.

Special 

Study

2014-28-Day 

Dietary – rat 

[BSA]

mg/kg/day =

M: 0, 6.4, 30, 82, 732

F: 0, 8.6, 39, 120, 1024

Acceptable/nonguideline

49387602 NOAEL (mg/kg/day): None

LOAEL (mg/kg/day): None

Aside from marginal (<25%) decreases in 

mean serum aspartate aminotransferase 

levels in both sexes and alanine 

aminotransferase levels in males at the high 

dose of 10,000 ppm, no treatment-related 

effects were observed in this study up to the 

highest dose tested.

Special 

Study

2014-28-Day 

Dietary – rat 

[TSA]

mg/kg/day =

M: 0, 10, 41, 113, 1194

F: 0, 12, 43, 123, 1779

Acceptable/nonguideline

49387601 NOAEL (mg/kg/day): None

LOAEL (mg/kg/day): None

No treatment-related effects were observed 

in this study up to the highest dose tested.

Special 

Study

2015-

comparative in 

vitro dermal 

absorption

mg/cm2 =

0.09 and 4.5 480 EC 

formulation.

49700504 The total absorption was calculated to be 

43.6% and 24.2% (low and high dose), and 

7.1% and 1.0% (low and high dose) for rat 

and human skin membranes, respectively.

Only new or modified toxicological parameters or points of departure are discussed here. 

Information related to other scenarios is available in D403767, M. Doherty et al., 18 June 2014.

A.3.4 Dermal Absorption

An in vivo dermal absorption study in the rat and two in vitro dermal absorption study using rat 

and human skin were submitted. All three studies used fluensulfone in an emulsifiableconcentrate (EC) formulation as the test material. The data demonstrated an inverse relationship 

between dosing concentration and percent absorption. Based on in vivo dermal absorption 

observed in the rat and in vitro comparative rat:human absorption data, an estimated human 

dermal absorption factor (DAF) was obtained as follows (all absorption values adjusted for 

recovery):

(1) In the rat in vivo dermal absorption study, a dermal absorption of 58.0% (directly 

absorbed plus absorbable) was found at 24 hrs post-exposure using an application of 

0.0953 mg/cm2; 

(2) In vitro exposure of split-thickness rat skin under the same exposure and assessment 

conditions gave a dermal absorption of 43.6% (directly absorbed plus absorbable); 

(3) The ratio of the rat in vitro to the rat in vivo absorption is 0.75 (43.6/58.0) which is 

close to 1, indicating that the in vitro data is predictive of in vivo absorption; 
Fluensulfone D427486

Page 54 of 57

(4) Based on this ratio, a DAF for humans may be calculated using in vitro human dermal 

absorption (7.1%, directly absorbed plus absorbable) observed in vitro under the same 

exposure conditions. The DAF for humans is therefore 7.1%/0.75= 9.5%.

A.3.5 Dermal Exposure (Short- and Intermediate-Term) 

Study Selected: 2-year toxicity/carcinogenicity study (rat).

MRID Nos: 48574765

Dose and Endpoint for Risk Assessment: NOAEL = 9.6 mg/kg/day based on decreased body 

weight in males, and hematology changes, clinical chemistry changes and histopathological 

effects in the lung and esophagus of both sexes at the LOAEL of 57.7 mg/kg/day.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factor: For short- and/or intermediate-term 

residential/occupational exposure scenarios involving dermal exposure, HED did not choose the 

28-day dermal toxicity study in rats conducted with the technical material. Although that study is 

of the appropriate route and duration, the results using the technical material do not appear to 

reflect the high dermal absorption of the emulsifiable concentrate (480 EC) observed in the in 

vivo and in vitro dermal penetrations studies. Given the lack of toxic response in the dermal 

toxicity study, HED has concluded that it is not representative of potential systemic exposure to 

fluensulfone from the 480 EC formulation, to which exposure would actually occur. Therefore, 

HED chose the chronic rat study discussed above, with a 9.5% dermal absorption factor to derive 

the point-of-departure. The chronic rat study was considered appropriate for short- and 

intermediate-term exposure as described above for incidental oral exposure. In addition to the 

rationale provided above, the 28-day rat and 90-day rat studies were not considered appropriate

for a dermal endpoint because the primary effects observed at the LOAEL in each study were 

either α-2-microglobulin induced kidney effects that are not relevant for human risk assessment 

(28- and 90-day rat) or portal-of-entry effects that would not be expected following dermal 

exposure (90-day rat).

A.3.6 Inhalation Exposure (Short- and Intermediate-Term) 

Study Selected: 90-day inhalation toxicity study in rats. 

MRID No: 48575045 

Executive Summary: See Appendix A.4, Guideline 870.3465 

Dose and Endpoint for Risk Assessment: NOAEL = not identified based on decreased weight 

gain in males, increased prothrombin time in females, decreased thymus weight in males and 

histopathology in the epiglottis in both sexes seen at LOAEL= 0.04 mg/L (lowest dose tested). 
Fluensulfone D427486

Page 55 of 57

HEC (occupational): rat NOAEL x (daily duration adjustment) x weekly daily duration 

adjustment x RDDR = 0.04 mg/L x (6 hr/8 hr) x (1) x 0.143 = 0.0043 mg/L.

HEC (residential handler): rat NOAEL x RDDR = 0.04 mg/L x 0.143 = 

0.0057 mg/L.

HED (occupational): HEC x conversion factor for breathing rate in L/hr-kg bw x human daily 

exposure duration in hours = 0.00429 mg/L x 11.8 L/hr-kg bw x 8 =0.41.

 

HED (residential handler): HEC x conversion factor for breathing rate in L/hr-kg bw x human

daily exposure duration in hours = 0.00572 mg/L x 11.8 L/hr-kg bw x 2 = 0.14 mg/kg/day.

Fluensulfone: HECs and HEDs: 90-day Subchronic Inhalation Study in Rats (MRID 49067003)

Short and 

intermediateterm 

Inhalation

Inhalation NOAEL = not 

identified

UFA= 3X

UFH =10X

UFL=10X

Residential and 

Occupational LOC 

for MOE = 300

Inhalation LOAEL = 0.04 

mg/L based on weight loss 

in males, prolonged 

prothrombin time in 

females, decreased thymus 

weight in males, 

histopathological changes 

in the epiglottis in both 

sexes, and 

histopathological changes 

in the nasal cavity of 

males.. 

Exposure Effect HECs HEDs

Occupational 

Handler 

HECs and 

HEDs

Portal of entry 0.0043 0.41

Systemic 0.077 7.3

Residential 

HECs and 

HEDs

Portal of entry 0.0057 0.14

Systemic 0.10 2.4

Uncertainty Factor: 300x (3x interspecies extrapolation, 10x intraspecies variability, 10x 

extrapolation from LOAEL to NOAEL)

Comments about Study/Endpoint/Uncertainty Factors: The 90-day inhalation toxicity study 

in rats was chosen because it is the only study available of the appropriate route and duration. An 

additional uncertainty factor of 10x for the extrapolation from a LOAEL to a NOAEL was 

applied. The interspecies uncertainty factor was reduced to 3x because of adjustment for species 

differences in pharmacokinetics.
Fluensulfone D427486

Page 56 of 57

Appendix B. Physical/Chemical Properties

Table B.1. Physicochemical Properties of the Technical Grade Fluensulfone

Parameter Value Reference

Molecular weight (g/mole) 291.7 EPA/PMRA joint review 

of fluensulfone technicalgrade active ingredient. 

Monograph Volume 3, 

Parts B1 and B2. B. 

Kitchens. December 2013.

Melting point/range (°C) 34.8 ± 0.5

pH 5.11 (1% solution at 21°C)

Density (g/cm3) 1.876

Water solubility ( g/L at 20°C) 0.5453

Organic solvent solubility (g/L at 20°C) Acetone 350.49

Dichloromethane 306.14

Ethyl acetate 350.76

n-Heptane 19.01

Methanol 359.29

n-Octanol 90.42

Xylene 356.18

Vapor pressure at 25°C (Pa) 3.0 x 10-2

Dissociation constant (pKa) No acidic or basic functional 

groups

Octanol/water partition coefficient Log(KOW) 2.2
Fluensulfone D427486

Page 57 of 57

Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

PHED 1.1 and the AHETF database are (1) subject to ethics review pursuant to 40 CFR 26, (2) 

have received that review, and (3) are compliant with applicable ethics requirements. For certain 

studies, the ethics review may have included review by the Human Studies Review Board. 

Descriptions of data sources, as well as guidance on their use, can be found at the Agency 

website4.

 

4 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html